Epigenome-wide association study of DNA methylation in maternal blood leukocytes with BMI in pregnancy and gestational weight gain.

OBJECTIVES: We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. METHODS: In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina's MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). RESULTS: We identified one CpG site significantly associated with GWG (p 5.8 × 10-8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10-8 to 2.1 × 10-10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10-8 to 0.04). CONCLUSIONS: We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits. GOV REGISTRATION NO: Not applicable.

Phenotypic and genotypic differences between Indian and Scandinavian women with gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. METHODS: Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). RESULTS: Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. CONCLUSIONS: Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.

Pain reduction after total laparoscopic hysterectomy and laparoscopic supracervical hysterectomy among women with dysmenorrhoea: a randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of total laparoscopic hysterectomy compared with laparoscopic supracervical hysterectomy for alleviating dysmenorrhoea. DESIGN: Randomised blinded controlled trial. SETTING: Norwegian university teaching hospital. SAMPLE: Sixty-two women with dysmenorrhoea. METHODS: Participants randomised to either total laparoscopic hysterectomy (n = 31) or laparoscopic supracervical hysterectomy (n = 31). MAIN OUTCOME MEASURES: The primary outcome measure, measured 12 months after intervention, was reduction of cyclic pelvic pain (visual analogue scale, 0-10). Secondary outcome measures included patient satisfaction (visual analogue scale, 0-10) and quality of life (Short Form 36, 0-100). RESULTS: The groups were comparable at baseline. There was no difference in self-reported dysmenorrhoea at 12 months (mean 0.8 [SD 1.6] versus 0.8 [SD 2.0], P = 0.94). There was no difference in patient satisfaction (mean 9.3 [SD 1.5] versus 9.1 [SD 1.2], P = 0.66) or quality of life (mean 81.6 [SD 17.8] versus 80.2 [SD 18.0], P = 0.69). CONCLUSION: Improvement in dysmenorrhoea and quality of life as well as patient satisfaction were comparable in the medium term when comparing total laparoscopic hysterectomy with laparoscopic supracervical hysterectomy.

Nociceptive stimuli responses at different levels of general anaesthesia and genetic variability.

BACKGROUND: Changes in skin conductance (SC), clinical stress score (CSS), the bispectral index spectroscopy (BIS) index and the variation in the BIS index may be used to monitor responses to nociceptive stimuli. We wanted to examine these methods during noxious stimulation during general anaesthesia and if the responses were associated with variability in genes related to pain. METHODS: Sixty patients, given propofol to a BIS level of 40-50, were stimulated with standardised tetanic electrical stimuli during propofol infusion, plasma level of 3 µg/ml alone, or together with remifentanil target plasma level of 3 ng/ml or 10 ng/ml. The CSS, SC, BIS index and the variability of the BIS index were registered. The inter-individual variation in nociceptive responses was analysed for co-variation with genotypes of 89 single nucleotide polymorphisms from 23 candidate genes. RESULTS: During tetanic stimuli, CSS and SC increased significantly and were attenuated with increasing level of remifentanil, different from the BIS index and the variation in the BIS index. Polymorphisms in the P-glycoprotein (ABCB1), tachykinin 1 receptor (TACR1), dopamine receptor D3 (DRD3) and beta arrestin 2 (ARRB2) genes were associated with the co-variation in SC variables or CSS response or both during standardised nociceptive stimuli (P < 0.05). Because of no corrections for multiple testing, the genetic analyses are explorative, and associations must be tested in further studies. CONCLUSION: This exploratory study suggests genes that may be tested further with relation to nociceptive response during anaesthesia. SC and CSS may be useful tools for monitoring nociceptive response during general anaesthesia.

A comparison of oxycodone prolonged-release vs. oxycodone + naloxone prolonged-release after laparoscopic hysterectomy.

BACKGROUND: Targiniq®, an oxycodone prolonged-release (PR) formulation combined with the opioid antagonist naloxone PR, aims to prevent opioid-induced constipation without impairing the analgesic efficacy. This has been confirmed during prolonged use in chronic pain or cancer patients. The purpose of our study was to compare clinical effects of oxycodone PR with oxycodone PR + naloxone PR for short-term post-operative pain management. METHODS: This randomised, double-blind, prospective study included 85 women undergoing laparoscopic hysterectomy. The two groups received either oxycodone PR 10 mg or oxycodone PR 10 mg + naloxone PR 5 mg as pre-medication and twice daily for 3 days. As rescue analgesic, the patients received oxycodone intravenous during the first 24 h post-operatively and oxycodone tablets in the 24-72-h period. Constipation, other side effects, pain and satisfaction were registered during the first 7 post-operative days. RESULTS: Demographic, pre- and perioperative variables and the use of rescue analgesics were similar in the groups. There were no significant differences in variables related to constipation. In the oxycodone PR + naloxone PR group, 25% had no defecation during the first 72 h post-operatively, compared with 20% in the oxycodone PR group (mean 1.2 ± 1.1 vs. 2.1 ± 2.4 defecations). Other opioid-induced effects and side effects showed no significant differences. Only 7% were dissatisfied with their oral pain treatment. CONCLUSION: Addition of naloxone to oxycodone PR tablets in a pain regimen administered twice daily the first three post-operative days had no significant clinical effects on constipation or other variables during the first week after hysterectomy.

Identification, at the genomic level, of an HLA-DR restriction element for cloned antigen-specific T4 cells.

Two T4 cell clones (TLC) specific for antigenic epitopes on Chlamydia trachomatis were studied. Using a panel of allogeneic antigen-presenting cells (APC), both TLC were found to be restricted by HLA class II elements closely associated with, but not identical to the DRw5S specificity, as determined by highly selected alloantisera, a monoclonal antibody (mAb), 109d6, and confirmed on the DNA level by determination of restriction fragment length polymorphisms (RFLP) with a DR beta probe. Furthermore, HLA-DR-specific mAb, including 109d6, but not other HLA class II- or class I-specific antibodies inhibited the two TLC, strongly suggesting that the restriction element is expressed by a DR molecule. Using digestion with Hind III restriction enzyme and a DR beta probe, we found a complete concordance between the appearance of a 9.3 kilobase band and the ability of allogeneic APC to restimulate the T cell clones. Thus, the restriction element for these T cell clones appear to be expressed by DR molecules, but can, at present, only be detected at the genomic level.

A combination of misoprostol and estradiol for preoperative cervical ripening in postmenopausal women: a randomised controlled trial.

OBJECTIVE: To compare the impact of 1000 microg of self-administered vaginal misoprostol versus self-administered vaginal placebo on preoperative cervical ripening after 2 weeks of pretreatment with estradiol vaginal tablets in postmenopausal women prior to day-care operative hysteroscopy. DESIGN: Randomised, double-blind, placebo-controlled sequential trial. SETTING: Norwegian university teaching hospital. POPULATION: Sixty-seven postmenopausal women referred for day-care operative hysteroscopy. METHODS: The women were randomised to receive either 1000 microg of self-administered vaginal misoprostol or self-administered vaginal placebo on the evening before day-care operative hysteroscopy. All women had administered a 25-microg vaginal estradiol tablet daily for 14 days prior to the operation. PRIMARY OUTCOME: preoperative cervical dilatation at hysteroscopy. SECONDARY OUTCOMES: difference in dilatation at recruitment and before hysteroscopy, number of women who achieved a preoperative cervical dilatation of 5 mm or more, acceptability, complications and adverse effects. RESULTS: The mean cervical dilatation was 5.7 mm (SD, 1.6 mm) in the misoprostol group and 4.7 mm (SD, 1.5 mm) in the placebo group, the mean difference in cervical dilatation being 1.0 mm (95% CI, 0.2-1.7 mm). Self-administered vaginal misoprostol of 1000 microg at home on the evening before day-care hysteroscopy is safe and highly acceptable, although a small proportion of women experienced lower abdominal pain. CONCLUSIONS: One thousand micrograms of self-administered vaginal misoprostol, 12 hours prior to day-care hysteroscopy, after 14 days of pretreatment with vaginal estradiol, has a significant cervical ripening effect compared with placebo in postmenopausal women.

Beneficial effects of K-ATP channel openers in diabetes: an update on mechanisms and clinical experiences.

Stresses associated with the diabetic state participate in the demise of beta-cells and therapies that eliminate or reduce such stresses are much needed. K-ATP channel openers, of which diazoxide is the most studied, are potentially useful because experimental studies show that they can counteract chronic over-stimulation of beta-cells and protect against toxic conditions, including relative hypoxia. Several mechanisms may underlie the beneficial effects of diazoxide; these may include both indirect (counteracting over-stimulation) and direct mitochondrial effects. Side effects of diazoxide have limited its use in human trials. We have tested lower doses than previously of diazoxide and thereby largely eliminated side effects. In this setting, we demonstrate positive effects on beta-cell function in type 2 diabetic patients who were simultaneously treated with bedtime insulin. However, such effects were absent in insulin-naïve patients. In newly diagnosed type 1 diabetic patients, a 6-month intervention with diazoxide failed to result in better preservation of beta-cell function. K-ATP channel openers have a potential to improve beta-cell function in subgroups of type 2 diabetes patients. Analogues of diazoxide with more potency in relation to side effects would heighten the possibilities for K-ATP channel openers to be of therapeutic use in type 1 diabetes.

Comparison of self-administered vaginal misoprostol versus placebo for cervical ripening prior to operative hysteroscopy using a sequential trial design.

OBJECTIVE: To compare the impact of 1000 micrograms of self-administered vaginal misoprostol versus self-administered vaginal placebo at home on preoperative cervical ripening in both premenopausal and postmenopausal women before operative hysteroscopy. DESIGN: Two separate but identical parallel, randomised, double-blind, placebo-controlled sequential trials, one in premenopausal women and one in postmenopausal women. The boundaries for the sequential trials were calculated on the primary outcomes of a difference of cervical dilatation > or = 1 mm, with the assumption of a type 1 error of 0.05 and a power of 0.95. SETTING: Norwegian university teaching hospital. SAMPLE: Eighty-six women referred to outpatient operative hysteroscopy. METHODS: The women were randomised to either 1000 micrograms of self-administered vaginal misoprostol or self-administered vaginal placebo the evening before outpatient operative hysteroscopy. MAIN OUTCOME MEASURES: Preoperative cervical dilatation (primary outcome), number of women who achieve a preoperative cervical dilatation > or = 5 mm, acceptability, complications and adverse effects (secondary outcomes). RESULTS: In premenopausal women, the mean cervical dilatation was 6.4 mm (SD 2.4) in the misoprostol group and 4.8 mm (SD 2.0) in the placebo group, the mean difference in cervical dilatation being 1.6 mm (95% CI 0.5-2.7). Among the premenopausal women receiving misoprostol, 88% achieved a cervical dilatation of > or = 5 mm compared with 65% in the placebo group. Twelve percent of the women who received misoprostol were difficult to dilate compared with 32% who received placebo. Dilatation was also quicker in the misoprostol group. Misoprostol had no effect on cervical ripening in postmenopausal women compared with placebo, and 43% of the women were difficult to dilate. The trials were terminated after analysis of 21 postmenopausal women and 65 premenopausal women after reaching a conclusion on the primary outcome with only 28% of the number of women needed in a fixed sample size trial. Three of 45 women who received misoprostol experienced severe lower abdominal pain, and there was an increased occurrence of light preoperative bleeding in the misoprostol group. Most women did not experience misoprostol-related adverse effects. The majority (83% of premenopausal and 76% of postmenopausal women) found self-administered vaginal misoprostol at home to be acceptable. There were two serious complications in the premenopausal misoprostol group: uterine perforation with subsequent peritonitis and heavy postoperative bleeding requiring blood transfusion, but these were not judged to be misoprostol related. Complications were otherwise comparatively minor and distributed equally between the two dosage groups. CONCLUSIONS: One thousand micrograms of self-administered vaginal misoprostol 12 hours prior to operative hysteroscopy has a significant cervical ripening effect compared with placebo in premenopausal but not in postmenopausal women. Self-administered vaginal misoprostol of 1000 micrograms at home the evening before operative hysteroscopy is safe and highly acceptable, although a small proportion of women experienced severe lower abdominal pain. There is a risk of lower abdominal pain and light preoperative bleeding with this regimen, which is very cheap and easy to use.

Long-term outcomes following laparoscopic supracervical hysterectomy.

OBJECTIVE: Evaluation of long-term outcomes following laparoscopic supracervical hysterectomy (LSH). DESIGN: Retrospective postal questionnaire. SETTING: Norwegian university teaching hospital. POPULATION: A total of 315 consecutive patients. METHODS: A questionnaire sent to all patients who underwent a LSH during 2004 and 2005. MAIN OUTCOME MEASURES: Persistent vaginal bleeding and pelvic pain, patient acceptability of such symptoms and patient satisfaction following LSH. RESULTS: A total of 240 women (78%) completed the questionnaire. About 24% reported experiencing vaginal bleeding up to 3 years following their hysterectomy, although this was rated as minimal in 90% of cases, resulting in a mean bothersome score of 1.1 (SD 2.0) on a 10-point visual analogue scale (VAS). Women operated on by less experienced surgeons were more likely to report vaginal bleeding following surgery (P = 0.02). About 74% of women reported having menstrual pain prior to surgery, with a mean score of 6.8 (SD 2.1) (10-point VAS). Up to 3 years following surgery, 38% continued to experience menstrual pain, although this was significantly less intense with a mean score of 3.5 (SD 2.2) (P < 0.01). While all women reported a decrease in the amount of pain experienced following the hysterectomy, those having a hysterectomy because of endometriosis reported significantly higher levels of menstrual/cyclical pain after surgery compared with women who had a hysterectomy for other reasons (P < 0.01). Ninety per cent of women reported being satisfied with their surgery. CONCLUSION: Although vaginal bleeding and pelvic pain are frequently observed following LSH, these symptoms are significantly reduced and patient satisfaction is high.

Differential impact of conventional and low-dose oral hormone therapy, tibolone and raloxifene on mammographic breast density, assessed by an automated quantitative method.

OBJECTIVE: To evaluate impact of different postmenopausal hormone therapy (HT) regimens and raloxifene on mammographic breast density. DESIGN: Open, randomised, comparative clinical trial. SETTING: Women were recruited through local newspapers and posters. They were examined at the Departments of Haematology, Gynaecology, and Radiology in a University Hospital. POPULATION: A total of 202 healthy postmenopausal women between the age of 45 and 65 years. METHODS: Women were randomly assigned to receive daily treatment for 12 weeks with tablets containing low-dose HT containing 1 mg 17 beta-estradiol + 0.5 mg norethisterone acetate (NETA) (n = 50), conventional-dose HT containing 2 mg 17 beta-estradiol and 1 mg NETA (n = 50), 2.5 mg tibolone (n = 51), or 60 mg raloxifene (n = 51). Mammographic density was determined at baseline and after 12 weeks by an automated technique in full-field digital mammograms. MAIN OUTCOME MEASURES: Mammographic density was expressed as volumetric breast density estimations. RESULTS: Mammographic breast density increased significantly and to a similar degree in both the conventional- and low-dose HT groups. A small reduction in mammographic breast density was seen in the raloxifene group, whereas those allocated to tibolone treatment only showed minor changes. CONCLUSIONS: Our findings demonstrated a significant difference in impact on mammographic breast density between the regimens. Although these results indicate a differential effect of these regimens on breast tissue, the relation to breast cancer risk remains unresolved.

Does self-administered vaginal misoprostol result in cervical ripening in postmenopausal women after 14 days of pre-treatment with estradiol? Trial protocol for a randomised, placebo-controlled sequential trial.

OBJECTIVE: To compare the impact of 1000 micrograms of self-administered vaginal misoprostol versus self-administered vaginal placebo on preoperative cervical ripening after pre-treatment with estradiol vaginal tablets at home in postmenopausal women prior to day-care operative hysteroscopy. DESIGN: Randomised double-blind placebo-controlled sequential trial. The boundaries for the sequential trial were calculated on the primary outcomes of a difference of cervical dilatation > or = 1 millimetre, with the assumption of a type 1 error of 0.05 and a power of 0.95. SETTING: Norwegian university teaching hospital. POPULATION: Postmenopausal women referred for day-care operative hysteroscopy. METHODS: The women were randomised to either 1000 micrograms of self-administered vaginal misoprostol or self-administered vaginal placebo the evening before day-care operative hysteroscopy. All women had administered a 25-microgram vaginal estradiol tablet daily for 14 days prior to the operation. MAIN OUTCOME MEASURES: Preoperative cervical dilatation (difference between misoprostol and placebo group, primary outcome), difference in dilatation before and after administration of misoprostol or placebo, number of women who achieve a preoperative cervical dilatation > or = 5 millimetres, acceptability, complications and side effects (secondary outcomes). RESULTS: Intra-operative findings and distribution of cervical dilatation in the two treatment groups: values are given as median (range) or n (%). Difference in dilatation before and after administration of misoprostol and placebo: values are given as median (range) of intraindividual differences. Percentage of women who achieve a cervical dilatation of > or = 5 mm, percentage of women who were difficult to dilate. Acceptability in the two treatment groups: values are given as completely acceptable n (%), fairly acceptable n (%), fairly unacceptable n (%), completely unacceptable n (%). Pain in the two treatment groups: pain was measured with a visual analogue scale ranging from 0 (no pain) to 10 (unbearable pain): values are given as median (range). Occurrence of side effects in the two treatment groups. Values are given as n (%). Complications given as n (%). FUNDING SOURCES: No pharmaceutical company was involved in this study. A research grant from the regional research board of Northern Norway has been awarded to finance Dr K.S.O.'s leave from Hammerfest hospital as well as travel expenses between Hammerfest and Oslo, and research courses. The research grant from Prof B.I.N. (Helse Øst) funded the purchase of estradiol tablets, the manufacturing costs of misoprostol and placebo capsules from the hospital pharmacy, as well as the costs incurred for preparing the randomisation schedule and distribution of containers containing capsules to hospital. Prof B.I.N.'s research grant also funded insurance for the study participants. CONCLUSIONS: Estimated completion date 31 December 2008.

Flow differences between endometrial polyps and cancer: a prospective study using intravenous contrast-enhanced transvaginal color flow Doppler and three-dimensional power Doppler ultrasound.

OBJECTIVES: To evaluate whether assessment of blood flow by transvaginal color Doppler and three-dimensional power Doppler imaging, enhanced by intravenous contrast, may be useful in the differentiation between benign endometrial polyps and endometrial cancer. METHODS: A prospective study was performed comparing 17 women with benign endometrial polyps and 17 women with endometrial cancer. Transvaginal color Doppler and three-dimensional power Doppler angiography were performed before and after injection of intravenous contrast. The pulsatility index (PI) and the resistance index (RI) of the polyp feeding vessel or central vessel in malignant lesions, as well as the power Doppler endometrial flow indices vascularization index (VI), flow index (FI) and vascularization flow index (VFI), were calculated before and after enhancement by contrast, and compared between the two groups of women. RESULTS: PI (mean difference +/- SD, 0.68 +/- 0.22; 95% CI, 0.23-1.13; P = 0.004) and RI (mean difference +/- SD, 0.16 +/- 0.08; 95% CI, 0.00-0.32; P = 0.045) were significantly lower in vessels of malignant tumors than in those of benign endometrial polyps after enhancement by intravenous contrast. No significant differences in PI, RI, VI, FI or VFI before enhancement by contrast, or in VI, FI or VFI after enhancement by contrast, were detected between women with endometrial polyps and those with endometrial cancer. CONCLUSIONS: Transvaginal color Doppler examination enhanced by intravenous contrast may help to discriminate between benign endometrial polyps and cancer. Larger studies are required to confirm these findings.

Effects of treatment with a 5-HT4 receptor antagonist in heart failure.

BACKGROUND AND PURPOSE: Positive inotropic responses (PIR) to 5-hydroxytryptamine (5-HT) are induced in the left ventricle (LV) in rats with congestive heart failure (CHF); this is associated with upregulation of the G(s)-coupled 5-HT(4) receptor. We investigated whether chronic 5-HT(4) receptor blockade improved cardiac function in CHF rats. EXPERIMENTAL APPROACH: Rats were given either the 5-HT(4) antagonist SB207266 (0.5 mg kg(-1) 24h(-1); MI(int)) or placebo (MI(pl)) through mini-osmotic pumps for 6 weeks subsequent to induction of post-infarction CHF. In vivo cardiac function and ex vivo responses to isoprenaline or 5-HT were evaluated using echocardiography and isolated LV papillary muscles, respectively. mRNA levels were investigated using real-time quantitative RT-PCR. KEY RESULTS: LV diastolic function improved, with 4.6% lower LV diastolic diameter and 24.2% lower mitral flow deceleration in MI(int) compared to MI(pl). SB207266 reduced LV systolic diameter by 6.1%, heart weight by 10.2% and lung weight by 13.1%. The changes in posterior wall thickening and shortening velocity, cardiac output, LV systolic pressure and (dP/dt)(max), parameters of LV systolic function, did not reach statistical significance. The PIR to isoprenaline (10 microM) increased by 36% and the response to 5-HT (10 microM) decreased by 57% in MI(int) compared to MI(pl). mRNA levels for ANP, 5-HT(4(b)) and 5-HT(2A) receptors, MHCbeta, and the MHCbeta/MHCalpha -ratio were not significantly changed in MI(int) compared to MI(pl). CONCLUSIONS AND IMPLICATIONS: Treatment with SB207266 to some extent improved in vivo cardiac function and ex vivo myocardial function, suggesting a possible beneficial effect of treatment with a 5-HT(4) receptor antagonist in CHF.

Comparison of self-administered vaginal misoprostol versus placebo for cervical ripening prior to operative hysteroscopy using a sequential trial design.

OBJECTIVE: To compare the impact of 1000-microgram self-administered vaginal misoprostol versus self-administered vaginal placebo at home on preoperative cervical ripening in both premenopausal and postmenopausal women prior to outpatient resectoscopy. DESIGN: Randomised, double-blind, placebo-controlled sequential trial. SETTING: Norwegian university teaching hospital. SAMPLE: Premenopausal and postmenopausal women referred to outpatient resectoscopy. METHODS: The women were randomised to either 1000 micrograms of self-administered vaginal misoprostol or self-administered vaginal placebo the evening before outpatient resectoscopy. MAIN OUTCOME MEASURES: Preoperative cervical dilatation, acceptability and complications. RESULTS: (a) Intraoperative findings and distribution of cervical dilatation in the two treatment groups. Values are given as median (range) or n (%). (b) Acceptability in the two treatment groups. Values are given as completely acceptable, n (%); fairly acceptable, n (%); fairly unacceptable, n (%) and completely unacceptable, n (%). (c) Pain in the two treatment groups. Pain was measured with a visual analogue scale score, scale ranges from 0 (no pain) to 10 (unbearable pain). Values are given as median (range). (d) Occurrence of adverse effects in the two treatment groups. Values are given as n (%). (e) Complications, given as n (%).

Conventional-dose hormone therapy (HT) and tibolone, but not low-dose HT and raloxifene, increase markers of activated coagulation.

OBJECTIVES: Hormone therapy (HT) is associated with a modest, but significantly increased risk for arterial and venous thromboembolism. We have compared the effects of estrogen, tibolone, and raloxifene on relevant markers of coagulation activation and investigated whether there is a dose-response relationship of oral HT. METHODS: Randomized, open-label, comparative study of 202 healthy women who were assigned to receive treatment for 12 weeks with either low-dose hormone therapy containing 1 mg 17beta-estradiol + 0.5 mg norethisterone acetate (NETA) (n=50), conventional-dose HT containing 2 mg 17beta-estradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51). RESULTS: The groups were comparable with regard to demographic characteristics and laboratory variables at baseline. D-dimer increased markedly in the conventional-dose HT group, but remained unchanged in the low-dose HT group. Tibolone was associated with a medium increase, whereas raloxifene was associated with a decrease in D-dimer levels. Changes in prothrombin fragment 1 + 2 showed a similar pattern for all four groups, whereas no significant differences in changes of thrombin-antithrombin complex were observed. CONCLUSIONS: Our data suggest that low-dose HT is associated with less activation of coagulation than conventional-dose HT. This finding may be of clinical importance since randomized clinical trials showing increased risk of thrombosis have utilized conventional-dose HT.

A novel technique of Roux-en-Y gastric bypass reversal for postprandial hyperinsulinemic hypoglycaemia: A case report.

BACKGROUND: We describe an evaluation of the effects of partial Roux-en-Y gastric bypass (RYGB) reversal on postprandial hyperinsulinaemic hypoglycaemia, insulin and GLP-1 levels. CASE SUMMARY: A 37 year old man was admitted with neuroglycopenia (plasma-glucose 1.6mmol/l) 18 months after RYGB, with normal 72h fasting test and abdominal CT. Despite dietary modifications and medical treatment, the hypoglycaemic episodes escalated in frequency. Feeding by a gastrostomy tube positioned in the gastric remnant did not prevent severe episodes of hypoglycaemia. A modified reversal of the RYGB was performed. Mixed meal tests were done perorally (PO), through the gastrostomy tube 1 (GT1), 4 weeks (GT2) after placement and 4 weeks after reversal (POr), with assessment of glucose, insulin and GLP-1 levels. RESULTS: Plasma-glucose increased to a maximum of 9.6, 5.4, 6.5 and 5.8mmol/l at the PO, GT1, GT2 and POr tests respectively. The corresponding insulin levels were 2939, 731, 725 and 463pmol/l. A decrease of plasma-glucose followed: 2.2, 3.0, 3.9 and 2.9mmol/l respectively and insulin levels were suppressed at 150min: 45, 22, 21 and 14pmol/l, respectively. GLP-1 levels increased in the PO test (60min: 122pmol/l, 21 fold of basal), but was attenuated in the two latter tests (12-23pmol/l at 60min). CONCLUSIONS: Reduction of plasma-glucose, insulin and GLP-1 excursions and symptoms were seen after gastric tube placement and partial RYGB reversal. This attenuation of GLP-1 response to feeding could reflect an adaptation to nutrients.

Cytotoxic T cells recognizing minor transplantation antigens, and possibly a variant of the HLA-B8 molecule. Cause of rejection of an HLA-identical sibling kidney transplant?

A male uremic patient was first transplanted with a kidney from a female cadaveric donor. The kidney was rejected after two weeks. He was retransplanted approximately one year later with a kidney from his HLA-identical sister. This graft was also irreversibly rejected after one week. No serum antibodies could be detected against the sibling donor before or after transplantation, but the recipient had formed donor-specific cytotoxic T lymphocytes (CTLs). The CTLs were cloned, and clones with two different specificities were obtained. One clone lysed target cells from the donor, from some other family members, and from 50% of a panel sharing HLA-B15 with the recipient. It may recognize a minor transplantation antigen, that is restricted by HLA-B15. The other clone lysed target cells from the donor, from all HLA-B8-positive family members (except the recipient), and from third-party cell donors sharing HLA-B8 with the recipient. When CTLs from third-party individuals were induced toward HLA-B8, target cells from all HLA-B8-positive family members were lysed, except those from the recipient. This indicates that the recipient may have inherited a variant of HLA-B8 that is not detectable by antibodies but by CTLs. These donor-specific CTLs may have contributed to the rejection of the HLA-identical sibling transplant.

Increased risk of recurrent venous thromboembolism during hormone replacement therapy--results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET).

Recent observational studies suggest a 2-4 fold increased risk of venous thromboembolism (VTE) in women taking hormone replacement therapy (HRT). The present study was started before publication of these studies, and the aim was to determine if HRT alters the risk of VTE in high risk women. The study was a randomized. double-blind, and placebo-controlled clinical trial with a double-triangular sequential design. Females with previously verified VTE were randomized to 2 mg estradiol plus 1 mg norethisterone acetate, 1 tablet daily (n = 71) or placebo (n = 69). The primary outcome was recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE). Between 1996 and 1998 a total of 140 women were included. The study was terminated prematurely based on the results of circumstantial evidence emerging during the trial. Eight women in the HRT group and one woman in the placebo group developed VTE. The incidence of VTE was 10.7% in the HRT group and 2.3% in the placebo group. In the HRT group, all events happened within 261 days after inclusion. The sequential design did not stop the study, but strongly indicated a difference between the two groups. Our data strongly suggests that women who have previously suffered a VTE have an increased risk of recurrence on HRT. This treatment should therefore be avoided in this patient group if possible. The results also support those of recent epidemiological studies, which also indicate increased risk of VTE in non-selected female populations during HRT.

The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism--results from a randomized, double-blind, clinical trial.

In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous thromboembolism (VTE), we found that hormone replacement therapy (HRT) was associated with an early excess risk of recurrent thrombosis. The aims of the present study were to characterize the effects of HRT on coagulation in these women to elucidate the mechanism(s) by which HRT increases the risk of thrombosis. The study comprised 140 women who were randomized to receive continuous treatment for 24 months with once daily 2 mg 17-beta-estradiol plus 1 mg norethisterone acetate (n = 71) or placebo (n = 69). HRT caused significant increases in prothrombin fragments 1+2, thrombin-antithrombin complex, and D-Dimer after 3 months, but these changes were less pronounced on prolonged treatment. The increases in markers of activated coagulation was higher in those women who subsequently developed recurrent thrombosis, but was similar in carriers and non-carriers of the factor V Leiden mutation. HRT had no effects on fibrinogen and factor VIII. Activated factor VII, but not factor VII antigen, decreased significantly on HRT as compared with placebo. The coagulation inhibitors antithrombin, protein C, and TFPI, but not protein S, all showed significant sustained decreases in the HRT group as compared with placebo. Antithrombin and protein C decreased by 8-12% on HRT, whereas TFPI activity decreased by 12-17% and TFPI free antigen by 29-30%. In multivariate analysis, only TFPI activity was a significant predictor for the increased activation of coagulation. We conclude that HRT was associated with early activation of coagulation, which corroborates the finding of an early risk of recurrent VTE. This activation may in part be explained by reduction in circulating anticoagulants.