Recent advances in placental peptide research: workshop report.
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Biomedical subjects
Publications and source records attributed to S Stock.
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Laparoscopic cholecystectomy was performed on a pregnant woman at 18 weeks of gestation without complications. Considering the risk/benefit ratio, laparoscopic cholecystectomy in pregnant women is preferable to conventional cholecystectomy.
A 2.5 kb DNA fragment of the Saccharomyces cerevisiae SYR1 gene was cloned by complementation of the syr1 mutations that simultaneously lead to resistance to the phytotoxin syringomycin and sensitivity of growth to high Ca2+ concentrations. Sequencing of this fragment revealed a single open reading frame encoding a polypeptide of 365 amino acids. Four hydrophobic regions each separated by hydrophilic regions were present in the protein. SYR1 was identical to ERG3, which is suggested to encode C-5 sterol desaturase required for ergosterol biosynthesis. The protein product of SYR1 was identified by Western blot analysis as a protein of 40 kDa in the particulate fraction. Gene disruption experiments demonstrated that elimination of SYR1/ERG3 is not lethal, but results in membrane C-5 desaturated sterol deficiencies, resistance to syringomycin and sensitivity to high Ca2+. The syr1 mutant cells had significantly decreased ability for syringomycin binding. The results indicated that C-5 desaturated sterols are involved in the binding of syringomycin to the cell, and the lack of the sterols in the mutant membrane results in sensitivity to high Ca2+ and an increased rate of cellular Ca2+ influx.
Pituitary growth hormone (GH), prolactin (PRL), placental lactogen (PL), insulin-like growth factor 1 (IGF-1) and GH-binding protein (GHBP) in plasma were determined in 12 women with gestational diabetes mellitus (GDM) and in 12 healthy pregnant women during a breakfast meal tolerance test. The women with GDM showed higher prepregnancy weight, body mass index (BMI), basal levels of glucose, insulin, and C peptide compared to the pregnant controls. No difference was found between the two groups in pituitary GH, PRL, PL and IGF-1 levels. Plasma levels of GHBP were higher in the women with GDM compared to pregnant controls. In all women there was an inverse correlation between PL and pituitary GH as well as between PL and GHBP, suggesting that PL inhibits pituitary GH secretion. A positive correlation between GHBP and BMI was found in all women, and the higher BMI in the GDM women seemed to be the cause of the higher GHBP levels in this group. In all women IGF-1, an indicator of the secretory activity of lactogenic hormones as well as of nutritional state, showed a positive correlation with the birth weights of the infants and was equally indicative in both groups.
Serum profiles of oxytocin were studied by means of a continuous blood sampling system in five young healthy women before and during treatment with a combined oral contraceptive. Oxytocin levels were determined by a specific radioimmunoassay in blood samples collected in 10-min fractions from 22.00 to 06.00. The values were further analyzed by the pulse detection program PULSAR. Great individual differences in oxytocin profiles were observed, and in some of the women these differences were also pronounced between the two sampling occasions. All 10 profiles demonstrated irregular peaks which occurred with varying frequency. Although the baseline level of oxytocin increased in all women and the average concentration increased in four of the women during treatment, there was no clear-cut effect on the peak frequency. Based on results from animal experiments, it is suggested that the increase in oxytocin levels may be related to an excitatory effect exerted by estrogen on oxytocin secreting neurons.
The regulation of oxytocin is incompletely understood and data indicate that in addition to several neurotransmitters, estrogens may be involved. The aim of the present study was to investigate the effects of oophorectomy and hormonal replacement therapy (HRT) on basal levels and 24-h profiles of oxytocin. Basal levels of oxytocin were measured in 95 women who had undergone hysterectomy and who were divided into three groups: group A (n = 30), oophorectomized (BSO), not on HRT; group B (n = 32), BSO, receiving HRT; and group C (n = 33), ovaries preserved and not receiving HRT. The 24-h profiles of oxytocin were measured in nine women before and after hysterectomy. Continuous venous blood sampling was performed 1 week before surgery and 6-7 weeks after surgery for all nine women. Thereafter, three of the four oophorectomized women started replacement therapy with transdermal estradiol 50 micrograms/day. After 10 weeks of treatment, a third sampling was performed. Exogenous estrogen administration was associated with increased oxytocin levels and negative correlation between oxytocin and follicle stimulating hormone/luteinizing hormone levels was found. Removal of the ovaries did not reduce oxytocin levels in any of the investigated groups. When 24-h values were analyzed, no specific rhythmic or pulsatile pattern before or after hysterectomy, with or without simultaneous oophorectomy, was found.
The present study assessed the possible role of oxytocin in the deterioration of glucose tolerance in gestational diabetes. Plasma levels of oxytocin, insulin, glucagon and glucose were measured at the time of a 400-kcal breakfast meal tolerance test in 12 women with gestational diabetes and 12 normal pregnant women in the third trimester. The gestational diabetic women had higher basal levels of insulin and an enhanced, delayed and prolonged insulin response to the breakfast. The same differences occurred in the glucose levels. There was no significant difference in the glucagon levels between the two groups. In the normal pregnant women, a significant (p < 0.05) though small rise in glucagon levels occurred 30 min after the ingestion of the breakfast. Oxytocin levels were not affected by the breakfast, and there was no clear difference between the two groups. The metabolic differences between the normal pregnant and gestational diabetic women were not related to any differences in oxytocin levels. In conclusion, we found no evidence of a role of oxytocin in the alteration of glucose metabolism in women with gestational diabetes. However, since alterations in oxytocin levels of possible significance for an impaired glucose tolerance are found in type 1 diabetic and extremely obese patients, further studies are needed in women with gestational or manifest diabetes.
The workshop was convened to develop quantitative estimates of the incidence of progressional musculoskeletal diseases in order to estimate the population health impact of arthritis. Estimates were developed for (a) the prevalence of arthritis, (b) a weighting strategy to adjust for the quality of life for the range of health states associated with arthritis, and (c) transition probabilities to represent the likelihood of disease onset and progression through the range of possible health states. A simulation "game" was designed to follow the progression of a cohort of 200 healthy persons or persons with arthritis, creating the basis for the estimation of transition probabilities and thus generating simulated longitudinal data that allow calculation of the quantitative estimate of the burden of illness from musculoskeletal diseases within the Canadian population.
Patients who continue to have or who develop abdominal pain after apparently successful cholecystectomy pose diagnostic difficulties. This study reports 384 such patients, investigated by endoscopic retrograde cholangiopancreatography (ERCP). There were 146 patients with abdominal pain alone with no previous history of common bile duct (CBD) exploration, of whom only 17 (11.6 per cent) had CBD stones on ERCP. Bile duct calculi were present in 76 of 140 patients (54.3 per cent) with abnormal biochemical findings (raised alkaline phosphatase and/or amylase level) and in 34 of 57 (60 per cent) with an abnormality detected on ultrasonography or intravenous cholangiography. A combination of biochemical and radiological abnormalities was present in 37 patients and was associated with CBD stones in 28 (76 per cent). Patients who had undergone CBD exploration represented a special group, of whom the majority (75 per cent) had common duct stones at ERCP even in the absence of biochemical and radiological abnormalities. ERCP is a useful investigation in patients with persistent postcholecystectomy symptoms. Other features in addition to pain or a history of CBD exploration may be relevant to the decision to perform ERCP in the investigation of these patients.
In 15 women investigated during the follicular, ovulatory and luteal phases of the menstrual cycle, only small variations in plasma levels of oxytocin were found. There was no mid-cycle surge in oxytocin levels. A parallel variation in oxytocin and oestradiol levels was found in five of the women. In 10 women examined every 4th week during gestation starting at week 12, a small but significant increase in oxytocin levels was found. Pronounced fluctuations in oxytocin levels were observed in four of the pregnant women. These fluctuations were independent of the stage of gestation and were also observed in three of the menstruating women. Seven out of 12 women treated with human menopausal gonadotrophin exhibited a marked elevation of oestradiol levels; oxytocin levels also increased and were significantly elevated when the oestradiol level exceeded 2 pmol/ml. Oxytocin levels were higher in the pregnant and human menopausal gonadotrophin-treated women than in the menstruating women. The oxytocin levels appeared to be only partly related to the oestradiol level. It is possible that the stimulatory effect of oestradiol is antagonized by a concomitantly high progesterone level. Alternatively, there may not be a linear dose-effect relationship between oestradiol and the release of oxytocin.
In the present investigation it was studied whether oxytocin administered directly in the pancreas of the rat stimulates the release of insulin and glucagon. In order to study such effects in vivo, a new experimental model applying the microdialysis technique was developed. To test the validity of the method, glucose or arginine were infused i.v. and it was shown that perfusate concentrations of insulin and glucagon increased significantly to 344 and 292% of basal overflow, respectively. Administration of oxytocin via the dialysis probe into the splenic portion of the pancreas resulted in significant elevations of insulin and glucagon concentrations to 210 (P less than 0.05) and 528% (P less than 0.01), respectively. The present study also includes a combined autoradiographic and immunohistochemical investigation of binding sites for oxytocin in the rat pancreas. A high density of [3H]oxytocin binding was present in the periphery of the islets of Langerhans, corresponding to the localization of the glucagon-producing alpha-cells. Both oxytocin and arginine(A)-vasopressin displaced [3H]oxytocin. The IC50 values were 10 and 180 nM, respectively. In conclusion, the oxytocin-induced release of insulin and glucagon as previously demonstrated in a number of species, may be due to a stimulation exerted by the peptide directly within the pancreas.
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The aim of the present study was to investigate how infusion of gastrin-17 and oxytocin affects plasma levels of insulin, glucagon and glucose in order to elucidate how the two hormones contribute to metabolic changes seen in situations where they are released, e.g. feeding and suckling during lactation. Thus, gastrin-17 (0.5 and 2.0 nmol kg-1 h-1) and oxytocin (0.11 and 1.1 nmol kg-1 h-1) were infused separately or simultaneously into conscious dogs. Both gastrin-17 and oxytocin induced significant, dose-dependent increases in insulin levels. An additive effect on insulin levels was obtained when gastrin-17 and oxytocin were infused simultaneously. Glucagon levels were not affected by gastrin-17 whereas infusion of 1.1 nmol kg-1 h-1 of oxytocin was followed by a significant increase. In contrast to a slight transient increase in the glucose level induced by oxytocin, infusion of gastrin-17 caused a sustained period of hypoglycaemia. Thus, infusion of gastrin-17 and oxytocin, respectively, gave rise to different ratios between circulating concentrations of insulin and glucagon reflected in different effects on the glucose level. The gastrin-induced hypoglycaemia could reflect that gastrin, via a release of insulin, promotes storing of glucose, e.g. in connection with feeding. That infusion of oxytocin caused a parallel increase in insulin and glucagon levels together with a slight increase in the glucose level could imply that oxytocin favours mobilization of glucose, e.g. during lactation.
The aim of the present study was to investigate whether plasma levels of gastrin, somatostatin, insulin, oxytocin, VIP and blood glucose levels vary during the menstrual cycle. Therefore, 19 healthy menstruating women (5 of whom were on low-dose oral contraceptives, o.c.) were blood sampled every second to third day during the menstrual cycle. Hormone levels were measured with radio-immunoassay. Gastrin, insulin, VIP and blood sugar levels remained unchanged during the menstrual cycle. Mean somatostatin levels were significantly lower in women receiving o.c. than in women without such medication (p less than 0.05). In women on o.c., somatostatin concentrations were also significantly lower during the menstrual week, than during the rest of the period (p less than 0.01), but in women without o.c., no such change occurred. Mean oxytocin levels were significantly higher in women on o.c. (p less than 0.001) and in these women, oxytocin levels recorded during the menstrual week were significantly lower than during the rest of the period (p less than 0.02). Systolic and diastolic blood pressure values were also significantly higher in women on o.c. (p less than 0.05 and p less than 0.01). In conclusion, these data show that basal plasma concentrations of gastrin, somatostatin, VIP, insulin and glucagon do not vary during the menstrual cycle. However, ingestion of low-dose oral contraceptives causes a significant decrease of somatostatin concentrations and a significant increase in oxytocin levels, suggesting that low doses of estrogens and/or gestagens may influence digestive and metabolic processes.
The effect of nipple stimulation on uterine activity, foetal heart rate and plasma oxytocin level in healthy full term pregnant women was studied. Ten women in weeks 38-39 of pregnancy stimulated their nipples for 30 min. Nine of the ten experienced uterine contractions. One woman showed signs uterine hyperactivity (frequent contractions) and foetal heart rate decelerations. Blood samples were drawn at 15 s intervals during 5-6 contractions and oxytocin levels were measured with radioimmunoassay. Oxytocin levels rose significantly during the nipple stimulation and short bursts of oxytocin were recorded during contractions. Nipple stimulation has been used to induce labour and our data may suggest that oxytocin released in response to such stimulation is responsible for the contractions induced.
The aim of the present study was to investigate whether low-dose oral contraceptives affect oxytocin concentrations in plasma. Twenty women participated in an open cross-over study. Six consecutive blood samples were drawn twice, with a 4-week interval, in the luteal phase of the menstrual cycle when the women were/were not taking oral contraceptives. Plasma levels of oxytocin were analysed with a radio-immunoassay specific for oxytocin. A significant increase in oxytocin concentrations was observed following ingestion of oral contraceptives (p less than 0.02). Women with the highest oxytocin levels during a normal menstrual cycle increased their levels the most when on oral contraceptives. Analysis with high performance liquid chromatography demonstrated that immunoreactive oxytocin found in plasma, whether with or without oral contraceptives, co-eluted with synthetic oxytocin standard. An interesting possibility could be that the mental side effects and effects on glucose metabolism occurring after treatment with oral contraceptives might be related to elevated oxytocin levels, since metabolic and CNS effects of oxytocin are known.
Impaired glucose tolerance and hyperinsulinaemia are common features of obesity. Since oxytocin has been shown to influence glucose metabolism and insulin secretion, the objective of the present study was to investigate whether the plasma level of oxytocin is elevated in obese subjects and if so, whether it is affected by weight reduction following gastric banding. Repeated blood samples were collected in connection with ingestion of a liquid test meal from subjects weighing about 130 kg. Normal weight subjects were tested likewise. Further tests were performed on obese subjects 6 months after operation with gastric banding and a subsequent weight reduction of about 30 kg. Plasma levels of oxytocin were measured by radioimmunoassay. It was found that plasma levels of oxytocin were 4-fold higher in the obese subjects when compared to the control subjects. Analysis with high performance liquid chromatography demonstrated that the oxytocin-like material, as determined by radioimmunoassay, in extracted plasma from one obese subject coeluted with synthetic oxytocin standard. Ingestion of a test meal did not seem to influence oxytocin levels. The mean oxytocin level was equally elevated in male and female obese subjects. Following operation oxytocin levels decreased significantly, but were still significantly higher than in the control subjects. The mechanism behind the hyperoxytocinaemia and possible consequence of it remain obscure.
This study was performed in order to investigate whether activation of sensory fibres within the sciatic and vagal nerves might influence the release of oxytocin. In anaesthetized rats the sciatic and vagal nerves were stimulated electrically in an afferent direction with a variety of stimuli. Rats were also stroked on their backs or nociception was inflicted by pinching a foot. Plasma oxytocin levels were measured with a highly sensitive radioimmunoassay in samples drawn from the carotid artery. Afferent electrical stimulations of both sciatic and vagal nerves at 5 V, 0.2-2 ms and 3-10 Hz caused immediate significant elevations of oxytocin levels. Thus, basal levels increased by 30-184%. Furthermore, in response to touch and nociceptive stimuli, oxytocin levels rose by 181% and 206%, respectively. These data indicate that oxytocin can be released by stimulation of peripheral nerves originating in the skin and/or muscle and in the gastrointestinal tract and thus these organs may be involved in the control of oxytocin secretion.