Insulin resistance of pregnancy involves estrogen-induced repression of muscle GLUT4

Pregnancy is accompanied by hyperestrogenism, however, the role of estrogens in the gestational-induced insulin resistance is unknown. Skeletal muscle plays a fundamental role in this resistance, where GLUT4 regulates glucose uptake. We investigated: (1) effects of oophorectomy and estradiol (E2) on insulin sensitivity and GLUT4 expression. E2 (similar to 200 nM) for 7 days decreased sensitivity, reducing similar to 30% GLUT4 mRNA and protein (P< 0.05) and plasma membrane expression in muscle; (2) the expression of ER alpha and ER beta in L6 myotubes, showing that both coexpress in the same nucleus; (3) effects of E2 on GLUT4 in L6, showing a time- and dose-dependent response. High concentration (100 nM) for 6 days reduced similar to 25% GLUT4 mRNA and protein (P < 0.05). Concluding, E2 regulates GLUT4 in muscle, and at high concentrations, such as in pregnancy, reduces GLUT4 expression and, in vivo, decreases insulin sensitivity. Thus, hyperestrogenism may be involved in the pregnancy-induced insulin resistance and/or gestational diabetes. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Effects of hypertension on maternal adaptations to pregnancy: experimental study on spontaneously hypertensive rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

The role of adrenal steroidogenesis in arterial hypertension

Adrenal aldosterone production, the major regulator of salt and water retention, is discussed with respect to hypertensive diseases. Physiological aldosterone production is tightly regulated, either stimulated or inhibited, in the adrenal zona glomerulosa by both circulating factors and/or by locally derived endothelial factors. Arterial hypertension caused by volume overload is the leading clinical symptom indicating increased mineralocorticoid hormones. Excessive aldosterone production is seen in adenomatous disease of the adrenals. The balance between stimulatory/proliferative and antagonistic signaling is disturbed by expression of altered receptor subtypes in the adenomas. Increased aldosterone production without a detectable adenoma is the most frequent form of primary aldosteronism. Both increased sensitivity to agonistic signals and activating polymorphisms within the aldosterone synthase gene (CYP11B2) have been associated with excessive aldosterone production. 17alpha-Hydroxylase deficiency and glucocorticoidremediable aldosteronism can also cause excessive mineralocorticoid synthesis. In contrast, the severe form of pregnancy-induced hypertension, preeclampsia, is characterized by a compromised volume expansion in the presence of inappropriately low aldosterone levels. Initial evidence suggests that compromised CYP11B2 is causative, and that administration of NaCl lowered blood pressure in pregnant patients with low aldosterone availability due to a loss of function.

Pregnancy complications in hyperemesis-affected pregnancy:a large hospital database study

Objective: Vomiting in pregnancy is a common condition affecting 80% of pregnant women. Hyperemesis is at one end of the spectrum, seen in 0.5–2% of the pregnant population. Known factors such as nulliparity, younger age and high body mass indexare associated with an increased risk of this condition in the first trimester. Late pregnancy complications attributable to hyperemesis, the pathogenesis of which is poorly understood, have not been studied in large population-based studies in the United Kingdom. The objective of this study was to determine a plausible association between hyperemesis and pregnancy complications,such as pregnancy-related hypertension, gestational diabetes and liver problems in pregnancy, and the rates of elective (ElCS) and emergency caesarean section (EmCS). Methods: Using a database based on ICD-10 classification, anonymised data of admissions to a large multi-ethnic hospital in Manchester, UK between 2000 and 2012 were examined.Notwithstanding the obvious limitations with hospital database-based research, this large volume of datasets allows powerful studies of disease trends and complications.Results Between 2000 and 2012, 156 507 women aged 45 or under were admitted to hospital. Of these, 1111 women were coded for hyperemesis (0.4%). A greater proportion of women with hyperemesis than without hyperemesis were coded forhypertensive disorders in pregnancy such as pregnancy-induced hypertension, pre-eclampsia and eclampsia (2.7% vs 1.5%;P=0.001). The proportion of gestational diabetes and liver disorders in pregnancy was similar for both groups (diabetes:0.5% vs. 0.4%; P=0.945, liver disorders: 0.2% vs. 0.1%;P=0.662). Hyperemesis patients had a higher proportion of elective and emergency caesarean sections compared with the non-hyperemesis group (ElCS: 3.3% vs. 2%; P=0.002, EmCS: 5% vs.3%; P=0.00). Conclusions: There was a higher rate of emergency and elective caesarean section in women with hyperemesis, which could reflect the higher prevalence of pregnancy-related hypertensive disorders(but not diabetes or liver disorders) in this group. The factors contributing to the higher prevalence of hypertensive disorders arenot known, but these findings lead us to question whether there is a similar pathogenesis in the development of both the conditions and hence whether further study in this area is warranted.

Correlation between the Body Mass Index (BMI) of Pregnant Women and the Development of Hypotension after Spinal Anesthesia for Cesarean Section

Nani FS, Torres MLA - Correlation between the Body Mass Index (BMI) of Pregnant Women and the Development of Hypotension after Spinal Anesthesia for Cesarean Section. Background and objectives: Very few publications correlate hypotension in obese pregnant women, and especially morbidly obese, after spinal anesthesia for cesarean section. The objective of the present study was to evaluate the incidence of hypotension according to the BMI. Methods: Forty-nine patients with pregestational BMI below 25 kg.m(-2) were included in the Eutrophia group, and 51 patients with BMI >= 25 kg.m(-2) were included in the Overweight group. After spinal anesthesia, blood pressure, volume of crystalloid infused, and dose of vasopressors used until delivery were recorded. A fall in systolic blood pressure below 100 mmHg or 10% reduction of the initial systolic blood pressure (SBP) was considered as hypotension and it was corrected by the administration of vasopressors. Results: Episodes of hypotension were fewer in the Eutrophia group (5.89 +/- 0.53 vs. 7.80 +/- 0.66, p = 0.027), as well as the amount of crystalloid administered (1,298 +/- 413.6 mL vs. 1,539 +/- 460.0 mL; p = 0.007), and use of vasopressors (5.87 +/- 3.45 bolus vs. 7.70 +/- 4.46 bolus; p = 0.023). As for associated diseases, we observed higher incidence of diabetes among obese pregnant women (29.41% vs. 9.76%, RR 1.60, 95%CI: 1.15-2.22, p = 0.036), however, differences in the incidence of pregnancy-induced hypertension (PIN) were not observe between both groups (overweight: 21.57%, normal weight: 12.20%, RR 1.30, 95%CI: 0.88-1.94, p = 0.28). Conclusions: In the study sample, pregestational BMI >= 25 kg.m(-2) was a risk factor for hypotension after spinal anesthesia in patients undergoing cesarean section. The same group of patients required higher doses of vasopressors. Those results indicate that the anesthetic techniques in those patients should be improved to reduce the consequences of post-spinal anesthesia hypotension, both in pregnant women and fetuses.

Comparative study on antioxidant effects and vascular matrix metalloproteinase-2 downregulation by dihydropyridines in renovascular hypertension

The vascular remodeling associated with hypertension involves oxidative stress and enhanced matrix metalloproteinases (MMPs) expression/activity, especially MMP-2. While previous work showed that lercanidipine, a third-generation dihydropyridine calcium channel blocker (CCB), attenuated the oxidative stress and increased MMP-2 expression/activity in two-kidney, one-clip (2K1C) hypertension, no previous study has examined whether first- or second-generation dihydropyridines produce similar effects. We compared the effects of nifedipine, nimodipine, and amlodipine on 2K1C hypertension-induced changes in systolic blood pressure (SBP), vascular remodeling, oxidative stress, and MMPs levels/activity. Sham-operated and 2K1C rats were treated with water, nifedipine 10 mg/kg/day, nimodipine 15 mg/kg/day, or amlodipine 10 mg/kg/day by gavage, starting 3 weeks after hypertension was induced. SBP was monitored weekly. After 6 weeks of treatment, quantitative morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin-stained sections. Aortic and systemic reactive oxygen species levels were measured by using dihydroethidine and thiobarbituric acid-reactive substances (TBARs), respectively. Aortic MMP-2 levels and activity were determined by gelatin zymography, in situ zymography, and immunofluorescence. Nifedipine, nimodipine, or amlodipine attenuated the increases in SBP in hypertensive rats by approximately 17% (P<0.05) and prevented vascular hypertrophy (P<0.05). These CCBs blunted 2K1C-induced increases in vascular oxidative stress and plasma TBARs concentrations (P<0.05). All dihydropyridines attenuated the increases in aortic MMP-2 levels and activity associated with 2K1C hypertension. These findings suggest lack of superiority of one particular dihydropyridine, at least with respect to antioxidant effects, MMPs downregulation, and inhibition of vascular remodeling in hypertension.

Brain natriuretic peptide: Disease marker or more in cardiovascular medicine?

Brain natriuretic peptide (BNP) is predominantly a cardiac ventricular hormone that promotes natriuresis and diuresis, inhibits the renin-anglotensin-aldosterone axis, and is a vasodilator. Plasma BNP levels are raised in essential hypertension, and more so in left ventricular (LV) hypertrophy and heart failure. Plasma BNP levels are also elevated in ischemic heart disease. Attempts have been made to use plasma BNP levels as a marker of LV dysfunction, but these have shown that plasma BNP levels are probably not sensitive enough to replace echocardiography in the diagnosis of LV dysfunction. Pericardial BNP or N-BNP may be more suitable markers of LV dysfunction. Plasma BNP levels are also elevated in right ventricular dysfunction, pregnancy-induced hypertension, aortic stenosis, age, subarachnoid hemorrhage, cardiac allograft rejection and cavopulmonary connection, and BNP may have an important pathophysiological role in some or all of these conditions. Clinical trials have demonstrated the natriuretic, diuretic and vasodilator effects, as well as inhibitory effects on renin and aldosterone of infused synthetic human BNP (nesiritide) in healthy humans. BNP infusion improves LV function in patients with congestive heart failure via a vasodilating and a prominent natriuretic effect. BNP infusion is useful for the treatment of decompensated congestive heart failure requiring hospitalization. The clinical potential of BNP is limited as it is a peptide and requires infusion. Drugs that modify the effects of BNP are furthering our understanding of the pathophysiological role and clinical potential of BNP. Increasing the effects of BNP may be a useful therapeutic approach in heart failure involving LV dysfunction. The levels of plasma BNP are increased by blockers, cardiac glycosides and vasopeptidase inhibitors, and this may contribute to the usefulness of these agents in heart failure. (C) 2001 Prous Science. All rights reserved.

Incretin receptor null mice reveal key role of GLP-1 but not GIP in pancreatic beta cell adaptation to pregnancy.

Islet adaptations to pregnancy were explored in C57BL6/J mice lacking functional receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Pregnant wild type mice and GIPRKO mice exhibited marked increases in islet and beta cell area, numbers of medium/large sized islets, with positive effects on Ki67/Tunel ratio favouring beta cell growth and enhanced pancreatic insulin content. Alpha cell area and glucagon content were unchanged but prohormone convertases PC2 and PC1/3 together with significant amounts of GLP-1 and GIP were detected in alpha cells. Knockout of GLP-1R abolished these islet adaptations and paradoxically decreased pancreatic insulin, GLP-1 and GIP. This was associated with abolition of normal pregnancy-induced increases in plasma GIP, L-cell numbers, and intestinal GIP and GLP-1 stores. These data indicate that GLP-1 but not GIP is a key mediator of beta cell mass expansion and related adaptations in pregnancy, triggered in part by generation of intra-islet GLP-1.

Exposition aux immunosuppresseurs in utero [Exposure in utero to immunosuppressives]

The number of pregnant women receiving immunosuppressive therapy is increasing. Use of immunosuppressants during pregnancy is indicated for anti-rejection therapy in transplantation patients and treatment of autoimmune diseases. Despite the maternal and fetal risks of these pregnancies, the proportion of surviving infants is improving and the possibility that a pregnancy could occur in these women during their childbearing years should be considered. All immunosuppressant drugs and their metabolites cross the placenta, raising questions about the long-term outcome of the children exposed to these agents in utera. There is no increased risk of congenital anomalies. However, there is an elevated incidence of prematurity, intrauterine growth retardation (IUGR) and therefore low birthweight, as well as maternal hypertension and preeclampsia. The most frequent neonatal complications are those associated with prematurity and IUGR, as well as adrenal insufficiency with corticosteroids, immunological disturbances with azathioprine and cyclosporin, and hyperkalemia with tacrolimus. The long-term follow-up of infants exposed to immunosuppressants in utero is still limited and experimental studies raise the question whether there could be an increased incidence at adult age of some pathologies including renal insufficiency, hypertension and diabetes. The follow-up of these infants should be carefully organized and multidisciplinary, taking the perinatal context into account.

Meédicaments: une cause sous-estimée d'hypertension artérielle [Drugs: an underestimated cause of arterial hypertension].

In Switzerland, as in other Occidental countries, the prevalence of arterial hypertension (AHT) in the adult population is around 30-40%. Among the causes of secondary AHT, drug induced hypertension is sometimes omitted. Many molecules can induce AHT or worsen it due to an interaction with anti hypertensive drugs. Among these, NSAIDs and anti depressants, widely prescribed, should be used with caution, particularly in patients at risk, namely: those with preexisting AHT, the elderly, or patients suffering from kidney disease, diabetes, and/or heart failure. Increases in blood pressure have also been described with anti-vascular endothelial growth factor (VEGF) drugs, used in the treatment of (metastatic) cancer. A thorough anamnesis of drugs, including over the counter ones, should be performed in every hypertensive patient, and can avoid cumbersome and unnecessary investigations and therapy.

Severe hypertension following accidental clonidine overdose during the refilling of an implanted intrathecal drug delivery system.

BACKGROUND:   Complications associated with intrathecal pumps may be linked to the surgical procedure, the implanted device, or the medication itself.¦CASE REPORTS:   Three patients treated chronically with intrathecal clonidine presented with clonidine overdose due to inadvertent extravasation during the refilling procedure. All patients experienced loss of consciousness and severe systemic hypertension that required aggressive parenteral treatment.¦DISCUSSION:   Clonidine is an alpha-2 agonist with a nearly 100% bioavailability after oral or rectal administration. With high plasma concentration secondary to massive systemic overdose, the specificity for the alpha-2 receptor is lost and an alpha-1 agonist activity predominates and causes marked hypertension. Management of clonidine overdose consists of supportive therapy guided by signs and symptoms.¦CONCLUSION:   Inadvertent injection into the subcutaneous pocket rather than the reservoir is rare but very dangerous as the drug cannot be retrieved and massive doses are involved. Signs and symptoms of systemic overdose with drugs commonly used in implanted drugs delivery system should be well known to ensure early diagnosis and treatment.

Influence of Assisted Reproductive Techniques in the occurrence of weight discordance in twin gestations

Background:There is no actual evidence that the ART are directly related to the occurrence of weight discordance. In some studies, ART-­‐conceived twin pregnancies are at greater risk than non-­‐ART-­‐conceived ones for pregnancy complications and adverse perinatal outcome: the incidences of pregnancy-­‐induced hypertension, uterine bleeding, premature contractions, IUGR, fetal death, discordance, and cesarean section were significantly higher. Discordance rate was elevated (25.3% vs.17.0%) among ART twins, which can increase perinatal risk (increased incidence of SGA and NICU admission). Other studies say that perinatal and neonatal morbidity, gestational age at delivery, and birth weight are not affected by ART. Regarding the first trimester ultrasound, some studies didn’t notice significant differences in CRL disparity or birth weight discordance between spontaneous and ART-­‐ conceived dichorionic twin pregnancies. In ART-­‐conceived dichorionic twin pregnancies, CRL disparity may be associated with birth weight discordance. In some studies, CRL discordance in twin pregnancies in the first trimester was a frequent finding. Objectives: To analyze the association of the ART in the occurrence of weight discordance in the pregnancies between 2010 and 2013 in the Hospital Universitari de Girona Doctor Josep Trueta, and to describe the proportion of diagnosis of growth discordance in the first trimester by the ultrasonography technology. Methods: A retrospective cohort study will be performed in those patients with twin pregnancies between 2010 and 2013, within the Hospital Universitari de Girona Doctor Josep Trueta (HUJT). A retrospective and descriptive study will be done in those cases with discordance weight in the moment of the birth, in which the CRL will be studied in the first trimester ultrasound, describing the percentage of discordance detected in that moment. The general characteristics of the sample are going to be analyzed by Logistic RegressionInfluenceof

Influence of Assisted Reproductive Techniques in the occurrence of weight discordance in twin gestations

Background:There is no actual evidence that the ART are directly related to the occurrence of weight discordance. In some studies, ART-­‐conceived twin pregnancies are at greater risk than non-­‐ART-­‐conceived ones for pregnancy complications and adverse perinatal outcome: the incidences of pregnancy-­‐induced hypertension, uterine bleeding, premature contractions, IUGR, fetal death, discordance, and cesarean section were significantly higher. Discordance rate was elevated (25.3% vs.17.0%) among ART twins, which can increase perinatal risk (increased incidence of SGA and NICU admission). Other studies say that perinatal and neonatal morbidity, gestational age at delivery, and birth weight are not affected by ART. Regarding the first trimester ultrasound, some studies didn’t notice significant differences in CRL disparity or birth weight discordance between spontaneous and ART-­‐ conceived dichorionic twin pregnancies. In ART-­‐conceived dichorionic twin pregnancies, CRL disparity may be associated with birth weight discordance. In some studies, CRL discordance in twin pregnancies in the first trimester was a frequent finding. Objectives: To analyze the association of the ART in the occurrence of weight discordance in the pregnancies between 2010 and 2013 in the Hospital Universitari de Girona Doctor Josep Trueta, and to describe the proportion of diagnosis of growth discordance in the first trimester by the ultrasonography technology. Methods: A retrospective cohort study will be performed in those patients with twin pregnancies between 2010 and 2013, within the Hospital Universitari de Girona Doctor Josep Trueta (HUJT). A retrospective and descriptive study will be done in those cases with discordance weight in the moment of the birth, in which the CRL will be studied in the first trimester ultrasound, describing the percentage of discordance detected in that moment. The general characteristics of the sample are going to be analyzed by Logistic RegressionInfluenceof

Influence of Assisted Reproductive Techniques in the occurrence of weight discordance in twin gestations

Background:There is no actual evidence that the ART are directly related to the occurrence of weight discordance. In some studies, ART-­‐conceived twin pregnancies are at greater risk than non-­‐ART-­‐conceived ones for pregnancy complications and adverse perinatal outcome: the incidences of pregnancy-­‐induced hypertension, uterine bleeding, premature contractions, IUGR, fetal death, discordance, and cesarean section were significantly higher. Discordance rate was elevated (25.3% vs.17.0%) among ART twins, which can increase perinatal risk (increased incidence of SGA and NICU admission). Other studies say that perinatal and neonatal morbidity, gestational age at delivery, and birth weight are not affected by ART. Regarding the first trimester ultrasound, some studies didn’t notice significant differences in CRL disparity or birth weight discordance between spontaneous and ART-­‐ conceived dichorionic twin pregnancies. In ART-­‐conceived dichorionic twin pregnancies, CRL disparity may be associated with birth weight discordance. In some studies, CRL discordance in twin pregnancies in the first trimester was a frequent finding. Objectives: To analyze the association of the ART in the occurrence of weight discordance in the pregnancies between 2010 and 2013 in the Hospital Universitari de Girona Doctor Josep Trueta, and to describe the proportion of diagnosis of growth discordance in the first trimester by the ultrasonography technology. Methods: A retrospective cohort study will be performed in those patients with twin pregnancies between 2010 and 2013, within the Hospital Universitari de Girona Doctor Josep Trueta (HUJT). A retrospective and descriptive study will be done in those cases with discordance weight in the moment of the birth, in which the CRL will be studied in the first trimester ultrasound, describing the percentage of discordance detected in that moment. The general characteristics of the sample are going to be analyzed by Logistic RegressionInfluenceof

Effects of pregnancy and protein-energy malnutrition on monooxygenase O-dealkylation activity in rat liver microsomes

Xenobiotic metabolism is influenced by a variety of physiological and environmental factors including pregnancy and nutritional status of the individual. Pregnancy has generally been reported to cause a depression of hepatic monooxygenase activities. Low-protein diets and protein-energy malnutrition have also been associated with a reduced activity of monooxygenases in nonpregnant animals. We investigated the combined effects of pregnancy and protein-energy malnutrition on liver monooxygenase O-dealkylation activity. On pregnancy day 0 rats were assigned at random to a group fed ad libitum (well-nourished, WN) or to a malnourished group (MN) which received half of the WN food intake (12 g/day). WN and MN rats were killed on days 0 (nonpregnant), 11 or 20 of pregnancy and ethoxy- (EROD), methoxy- (MROD) and penthoxy- (PROD) resorufin O-dealkylation activities were measured in liver microsomes. Only minor changes in enzyme activities were observed on pregnancy day 11, but a clear-cut reduction of monooxygenase activities (pmol resorufin min-1 mg protein-1) was noted near term (day 0 vs 20, means ± SD, Student t-test, P<0.05) in WN (EROD: 78.9 ± 15.1 vs 54.6 ± 10.2; MROD: 67.8 ± 10.0 vs 40.9 ± 7.2; PROD: 6.6 ± 0.9 vs 4.3 ± 0.8) and in MN (EROD: 89.2 ± 23.9 vs 46.9 ± 15.0; MROD: 66.8 ± 13.8 vs 27.9 ± 4.4; PROD: 6.3 ± 1.0 vs 4.1 ± 0.6) dams. On pregnancy day 20 MROD was lower in MN than in WN dams. Malnutrition did not increase the pregnancy-induced reduction of EROD and PROD activities. Thus, the present results suggest that the activities of liver monooxygenases are reduced in near-term pregnancy and that protein-energy malnutrition does not alter EROD or PROD in pregnant rats.