Safety and Efficacy of Oral Mifepristone in Pre-induction Cervical Ripening and Induction of Labour in Prolonged Pregnancy

Objective(S)

To study the safety and efficacy of oral mifepristone in pre-induction cervical ripening and induction of labour in prolonged pregnancy.

Method(S)

This is a single blind randomized control trial. 100 women with prolonged pregnancy beyond 40 weeks and Bishop score <6 were recruited, and randomly allocated into two groups. Women who received Tab. Mifepristone 200 mg orally were assigned in Study Group (n = 50) and who received placebo orally were assigned in Control Group (n = 50) At the end of 24 h, change in the Bishop’s score was assessed and Tab. Misoprostol 25 μg was administered intravaginally every 4 h, maximum 6 doses for induction/augmentation of labour. Analysis regarding safety and efficacy of the drug was done with regards to maternal and perinatal outcome.

Result(S)

Among 100 subjects, 50 received mifepristone and 50 received placebo. Mean induction to delivery interval was 1,907 ± 368.4 min for Study Group versus 2,079 ± 231.6 min for Control Group. The improvement in mean Bishop score was 5.0408 ± 1.90 for Study Group compared with 3.26 ± 1.15 was for Control Group after 24 h. Mean dose of misoprostol in Study Group was 40 ± 27.2, while the same in Control Group was 52 ± 19.46. Eight (16 %) women in Study Group and two (4 %) women in Control Group delivered vaginally within 24 h without any need of augmentation. There were 6 (12 %) cesareans and 2 (4 %) instrumental deliveries in Study Group and 8 (16 %) cesareans and 5 (10 %) instrumental deliveries in the Control Group. There was no statistically significant difference in perinatal outcomes between two groups.

Conclusion(S)

Mifepristone had a modest effect on cervical ripening when given 24 h prior to labour induction and appearing to reduce need for misoprostol compared with placebo.     

Secretion of goblet cell serine proteinase, ingobsin, is stimulated by vasoactive intestinal polypeptide and acetylcholine

Ingobsin is localized to the intestinal goblet cells in the rat and in man. In the present study, we investigated the effect of vasoactive intestinal polypeptide (VIP) and acetylcholine on the secretion of ingobsin from the proximal duodenum. Intravenous infusion of VIP or acetylcholine increased the concentration of ingobsin in duodenal secretion, while the concentration in the duodenum was unchanged. Simultaneous infusion of VIP and acetylcholine increased the concentration of ingobsin in duodenal secretion and decreased the concentration of ingobsin in the duodenum. This study demonstrates that secretion of ingobsin from the proximal duodenum is exocrine and can be stimulated by VIP and acetylcholine.     

Adrenergic effects on secretion of amylase from the rat salivary glands

The present study was undertaken to investigate the effect of adrenergic agents on secretion of amylase from the salivary glands in vivo. Saliva was collected from the distal oesophagus in conscious rats. Adrenaline increased the concentration of amylase in saliva and serum significantly. The result of infusion of alpha- and beta-adrenergic antagonists as well as noradrenaline and isoproterenol showed that secretion of salivary amylase is predominantly mediated by stimulation of beta-adrenergic receptors, especially of the beta 1-subtype. Investigation of the isoenzyme pattern in saliva, pancreatic juice and serum demonstrated that the major component in serum is salivary amylase. This study has shown that beta-adrenergic agents stimulate secretion of amylase from the salivary glands in rats. Though the secretion is mainly exocrine small amounts of amylase is found in serum, which seems to originate from the salivary glands.     

Prognosis of diabetics with diabetes onset before the age of thirtyone

Summary A follow-up on three hundred and seven patients diagnosed before 1933 and before the patient was thirty-one years old was conducted as of 1.1.1973, i.e. after at least forty years of diabetes. All patients were seen at the Steno Memorial hospital and were referred from all parts of Denmark. A small proportion of the patients (5.9%) could not be traced. Of the remaining two hundred and eightynine patients 40% were alive. Three-hundred and six patients were insulin dependent, 87% being treated with insulin twice daily. More than 50% survived their diabetes for more than thirty-five years. The mortality rate was 2–6 times that in an age- and sexmatched non-diabetic population. In 31% of the deceased patients the cause of death was uraemia; in 25% myocardial infarction. The excess mortality among patients exhibiting persistent proteinuria before forty years of diabetes was 3–4 times higher than in patients who did not have proteinuria after forty years.16% of the whole study population became blind, and another 14% had severely impaired vision; 21% exhibited objective signs of myocardial infarction, 10% of stroke, and 12% had gangrene or had undergone amputation of the foot or lower leg; 38% had proteinuria and 22% uraemia. Death with or from hypoglycaemia was more common than death in ketoacidotic coma. Clinical manifestations of late diabetic complications were considerably less common in patients who were still alive after more than forty years of diabetes than in patients who died before their fortieth year of diabetes.     

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

Aims/hypothesis

Energy-dense diets that are high in fat are associated with a risk of metabolic diseases. The underlying molecular mechanisms could involve epigenetics, as recent data show altered DNA methylation of putative type 2 diabetes candidate genes in response to high-fat diets. We examined the effect of a short-term high-fat overfeeding (HFO) diet on genome-wide DNA methylation patterns in human skeletal muscle.

Methods

Skeletal muscle biopsies were obtained from 21 healthy young men after ingestion of a short-term HFO diet and a control diet, in a randomised crossover setting. DNA methylation was measured in 27,578 CpG sites/14,475 genes using Illumina's Infinium Bead Array. Candidate gene expression was determined by quantitative real-time PCR.

Results

HFO introduced widespread DNA methylation changes affecting 6,508 genes (45%), with a maximum methylation change of 13.0 percentage points. The HFO-induced methylation changes were only partly and non-significantly reversed after 6–8 weeks. Alterations in DNA methylation levels primarily affected genes involved in inflammation, the reproductive system and cancer. Few gene expression changes were observed and these had poor correlation to DNA methylation.

Conclusions/interpretation

The genome-wide DNA methylation changes induced by the short-term HFO diet could have implications for our understanding of transient epigenetic regulation in humans and its contribution to the development of metabolic diseases. The slow reversibility suggests a methylation build-up with HFO, which over time may influence gene expression levels.     

Peptidomics approach to elucidate the proteolytic regulation of bioactive peptides

Peptide hormones and neuropeptides have important roles in physiology and therefore the regulation of these bioactive peptides is of great interest. In some cases proteolysis controls the concentrations and signaling of bioactive peptides, and the peptidases that mediate this biochemistry have proven to be extremely successful drug targets. Due to the lack of any general method to identify these peptidases, however, the role of proteolysis in the regulation of most neuropeptides and peptide hormones is unknown. This limitation prompted us to develop an advanced peptidomics-based strategy to identify the peptidases responsible for the proteolysis of significant bioactive peptides. The application of this approach to calcitonin gene-related peptide (CGRP), a neuropeptide associated with blood pressure and migraine, revealed the endogenous CGRP cleavage sites. This information was then used to biochemically purify the peptidase capable of proteolysis of CGRP at those cleavage sites, which led to the identification of insulin-degrading enzyme (IDE) as a candidate CGRP-degrading enzyme. CGRP had not been identified as an IDE substrate before and we tested the physiological relevance of this interaction by quantitative measurements of CGRP using IDE null (IDE(-/-)) mice. In the absence of IDE, full-length CGRP levels are elevated in vivo, confirming IDE as an endogenous CGRP-degrading enzyme. By linking CGRP and IDE, this strategy uncovers a previously unknown pathway for CGRP regulation and characterizes an additional role for IDE. More generally, this work suggests that this may be an effective general strategy for characterizing these pathways and peptidases moving forward.     

Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity

The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors. We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed by gene expression, mammosphere formation and lineage markers. Luminal-like cells without basal-like traits, surprisingly, were fully capable of initiating invasive tumors in NOD SCID gamma (NSG) mice. In fact, these phenotypically pure luminal-like cells generated larger and more invasive tumors than their basal-like counterparts. The tumorigenicity and invasive potential of the luminal-like cancer cells relied strongly on the expression of the gene GCNT1, which encodes a key glycosyltransferase controlling O-glycan branching. These findings demonstrate that basal-like cells, as defined currently, are not a requirement for breast tumor aggressiveness, and that within a single tumor there are multiple “stem-like” cells with tumorigenic potential casting some doubt on the hypothesis of hierarchical or differentiative loss of tumorigenicity.