VIP conditions human endometrial receptivity by privileging endoplasmic reticulum stress through ATF6α pathway.

Endometrial stromal cells undergo endoplasmic reticulum (ER) stress and unfolded protein response (UPR) during the decidualization linked with the inflammation and angiogenesis processes. Considering VIP (vasoactive intestinal peptide) induces the decidualization program, we studied whether modulates the ER/UPR pathways to condition both processes for embryo implantation. When Human Endometrial Stromal Cell line (HESC) were decidualized by VIP we observed an increased expression of ATF6α, an ER stress-sensor, and UPR markers, associated with an increase in IL-1ß production. Moreover, AEBSF (ATF6α -inhibitor pathway) prevented this effect and decreased the expansion index in the in vitro model of implantation. VIP-decidualized cells also favor angiogenesis accompanied by a strong downregulation in thrombospondin-1. Finally, ATF6α, VIP and VPAC2-receptor expression were reduced in endometrial biopsies from women with recurrent implantation failures in comparison with fertile. In conclusion, VIP privileged ATF6α-pathway associated with a sterile inflammatory response and angiogenesis that might condition endometrial receptivity.

Adipokine levels in overweight women with early-onset gestational diabetes mellitus.

PURPOSE: The study of adipokines in overweight women with early-onset (diagnosed before 20 weeks) gestational diabetes mellitus (GDM) could help to understand the ethiopathological mechanisms of this disorder. Our aim was to assess adipokine levels in overweight pregnant women with early-onset GDM compared to patients with standard-onset (diagnosed at 24-28 weeks) GDM and to glucose-tolerant women at the same gestational ages. METHODS: This nested case-control study included 133 overweight pregnant women: 33 with early-onset (diagnosed < 20 weeks) GDM; 40 with standard-onset (diagnosed ≥ 24 weeks) GDM and 60 glucose-tolerant (normal oral glucose tolerance tests < 20 and ≥ 24 weeks). Adiponectin, leptin, resistin, visfatin and ghrelin serum levels were measured by ELISA. RESULTS: Adiponectin serum levels were significantly lower in early-onset GDM women than in standard-onset GDM patients or controls matched for gestational age. Leptin serum levels were significantly higher in women with early-onset GDM than in controls. Women with early-onset GDM had lower adiponectin/leptin ratio than those with standard-onset GDM. There were no significant differences in resistin, ghrelin and visfatin serum levels among the participants. CONCLUSIONS: Our results suggest that, compared to overweight glucose-tolerant women and patients with standard-onset GDM, overweight women with early-onset GDM have unbalanced adipokine levels, suggesting that they have a more inflammatory profile.

Impact of the Reticular Stress and Unfolded Protein Response on the inflammatory response in endometrial stromal cells.

During decidualization, endometrial stromal cells undergo reticular stress (RS) and unfolded protein response (UPR), allowing the endoplasmic reticulum-expansion and immunomodulators production. Physiological RS generates the activation of sensing proteins, inflammasome activation and mature-IL-1ß secretion, associated with pro-implantatory effects. We focus on the impact of RS and UPR on decidualized cells and whether they induce a physiological sterile inflammatory response through IL-1ß production. Human endometrial stromal cell line (HESC) after decidualization treatment with MPA + dibutyryl-cAMP (Dec) increased the expression of RS-sensors (ATF6, PERK and IRE1α) and UPR markers (sXBP1 and CHOP) in comparison with Non-dec cells. Then we found increased NLRP3 expression in Dec cells compared with Non-dec cells. In fact STF-083010 (an IRE1α inhibitor) prevented this increase. Downstream, increased levels of active caspase-1 on Dec cells were detected by FAM-Flica Caspase-1 associated with an increase in IL-1ß production. Moreover, the treatment with STF-083010 decreased the invasion index observed in Dec cells, evaluated by an in vitro model of implantation. In endometrial biopsies from recurrent spontaneous abortion patients an increased expression of IRE1α was found in comparison with fertile women; while recurrent implantation failure samples showed a lower expression of sXBP1, TXNIP and NLRP3 than fertile women, suggesting that RS/UPR tenors might condition endometrial receptivity.

Impact of cesarean section in a private health service in Brazil: indications and neonatal morbidity and mortality rates.

OBJECTIVE: To evaluate the incidence of, indications of, and maternal and neonatal morbidity and mortality rates in cesarean sections in a private health service in Brazil. DESIGN: Retrospective and observational study. SETTING: Private health service in Vitória, Espírito Santo, Brazil. METHODS: The patients were interviewed using a structured questionnaire to determine maternal age, gestational age at the time of delivery, number of previous deliveries, type of delivery performed, duration of labor, indications for cesarean delivery, point at which cesarean section was performed, physician responsible for delivery, and maternal morbidity, fetal morbidity, and fetal mortality rates. A descriptive analysis of the data was conducted. Students t-test was performed to compare quantitative variables, and Fishers exact test was performed for categorical variables. RESULTS: A total of 584 patients were evaluated. Of these, 91.8% (536/584) had cesarean sections, while only 8.2% (48/584) had vaginal deliveries. There were no reports of forceps-assisted vaginal deliveries. In 87.49% of the deliveries, the number of gestational weeks was more than 37. In terms of indications for performing cesarean section, 48.5% were for maternal causes, 30.41% were for fetal causes, and 17.17% were elective. Maternal re-hospitalization due to puerperal complications was necessary in 10.42% of the vaginal deliveries and in 0.93% of the cesarean deliveries (p<0.001). Complications were observed in 18.75% of the vaginally delivered newborns and in 17.16% of those delivered by cesarean section. Of the newborns with complications at birth, 40.59% (41/101) had to be admitted to the neonatal intensive care unit. There were no cases of maternal death. There were seven cases of fetal/neonatal death. CONCLUSION: We observed that the vast majority of deliveries in the private sector are performed by cesarean section, without labor, and by the patients obstetrician. We found no serious maternal complications or increased neonatal morbidity rates associated with cesarean section.

Effects of cervical cerclage on cervical length and the impact of changes in cervical length on pregnancy prognosis.

OBJECTIVE: To identify any cervix-related morphological and functional marker that can be correlated with pregnancy prognosis in patients who have undergone cerclage for cervical incompetence. DESIGN: An observational and prospective study. SETTING: Department of Obstetrics, Paulista School of Medicine - Federal University of São Paulo (UNIFESP-EPM). METHODS: Patients with cervical incompetence who underwent cervical cerclage using a modified version of the McDonald procedure during or before the 22nd week of pregnancy. The patients were examined by transvaginal ultrasound in the preoperative period, the immediate postoperative period, and between 20 and 24 weeks, 24 weeks + 1 day and 28 weeks, and 28 weeks + 1 day and 32 weeks. Cervical length and the presence of funneling were evaluated during all examinations. Changes in cervical length, presence or absence of funneling, percent increase or decrease in cervical length, and cervical length of less than established values (.

Pamidronate for the treatment of osteoporosis secondary to chronic cholestatic liver disease in Wistar rats

Osteoporosis is a major complication of chronic cholestatic liver disease (CCLD). We evaluated the efficacy of using disodium pamidronate (1.0 mg/kg body weight) for the prevention (Pr) or treatment (Tr) of cholestasis-induced osteoporosis in male Wistar rats: sham-operated (Sham = 12); bile duct-ligated (Bi = 15); bile duct-ligated animals previously treated with pamidronate before and 1 month after surgery (Pr = 9); bile duct-ligated animals treated with pamidronate 1 month after surgery (Tr = 9). Rats were sacrificed 8 weeks after surgery. Immunohistochemical expression of IGF-I and GH receptor was determined in the proximal growth plate cartilage of the left tibia. Histomorphometric analysis was performed in the right tibia and the right femur was used for biomechanical analysis. Bone material volume over tissue volume (BV/TV) was significantly affected by CCLD (Sham = 18.1 ± 3.2 vs Bi = 10.6 ± 2.2%) and pamidronate successfully increased bone volume. However, pamidronate administered in a preventive regimen presented no additional benefit on bone volume compared to secondary treatment (BV/TV: Pr = 39.4 ± 12.0; Tr = 41.2 ± 12.7%). Moreover, the force on the momentum of fracture was significantly reduced in Pr rats (Sham = 116.6 ± 23.0; Bi = 94.6 ± 33.8; Pr = 82.9 ± 22.8; Tr = 92.5 ± 29.5 N; P < 0.05, Sham vs Pr). Thus, CCLD had a significant impact on bone histomorphometric parameters and pamidronate was highly effective in increasing bone mass in CCLD; however, preventive therapy with pamidronate has no advantage regarding bone fragility.

Pamidronate for the treatment of osteoporosis secondary to chronic cholestatic liver disease in Wistar rats.

Osteoporosis is a major complication of chronic cholestatic liver disease (CCLD). We evaluated the efficacy of using disodium pamidronate (1.0 mg/kg body weight) for the prevention (Pr) or treatment (Tr) of cholestasis-induced osteoporosis in male Wistar rats: sham-operated (Sham = 12); bile duct-ligated (Bi = 15); bile duct-ligated animals previously treated with pamidronate before and 1 month after surgery (Pr = 9); bile duct-ligated animals treated with pamidronate 1 month after surgery (Tr = 9). Rats were sacrificed 8 weeks after surgery. Immunohistochemical expression of IGF-I and GH receptor was determined in the proximal growth plate cartilage of the left tibia. Histomorphometric analysis was performed in the right tibia and the right femur was used for biomechanical analysis. Bone material volume over tissue volume (BV/TV) was significantly affected by CCLD (Sham = 18.1 ± 3.2 vs Bi = 10.6 ± 2.2%) and pamidronate successfully increased bone volume. However, pamidronate administered in a preventive regimen presented no additional benefit on bone volume compared to secondary treatment (BV/TV: Pr = 39.4 ± 12.0; Tr = 41.2 ± 12.7%). Moreover, the force on the momentum of fracture was significantly reduced in Pr rats (Sham = 116.6 ± 23.0; Bi = 94.6 ± 33.8; Pr = 82.9 ± 22.8; Tr = 92.5 ± 29.5 N; P < 0.05, Sham vs Pr). Thus, CCLD had a significant impact on bone histomorphometric parameters and pamidronate was highly effective in increasing bone mass in CCLD; however, preventive therapy with pamidronate has no advantage regarding bone fragility.

Interruption of a study of cervical ripening with isosorbide mononitrate due to adverse effects.

PURPOSE OF INVESTIGATION: The objective of this study was to evaluate cervix length and the presence of cervical gland area (CGA) in ultrasounds performed before and after the administration of vaginal isosorbide mononitrate (IMN) for cervical ripening. METHODS: We performed an observational, descriptive, and longitudinal study of pregnant patients indicated for labor induction and with a Modified Bishop Score (MBS) lower than six. For cervical ripening, 40 mg of vaginal IMN was administered at 0, 16, and 24 hours after the initiation of cervix preparation. RESULTS: After enrolling 11 patients, the study had to be discontinued due to adverse effects. Three patients requested that they be withdrawn. Headaches were reported by all patients. Nausea, dizziness, dyspnea, and vomiting were also reported. The average cervical lengths at 0, 16, 24 and 36 hours were 27.6, 27.7, 25.9, and 23.0 mm, respectively. CGA disappeared in one of seven patients. CONCLUSIONS: The use of IMN appears to increase the MBS, slightly reducing cervical length without altering the appearance of CGA. Considering the importance of maternal wellbeing during labor, the routine use of IMN cannot be recommended for cervical ripening in the third trimester due to the frequency and intensity of side-effects.

Diagnosis of ovarian metastasis from gestational trophoblastic neoplasia by 3D power Doppler ultrasound and dynamic contrast-enhanced magnetic resonance imaging: case report.

Choriocarcinoma is a highly malignant disease of trophoblastic cells, which affects young women in the reproductive years. The main sites of metastasis from choriocarcinoma are lung, vagina, liver, gastrointestinal tract and kidneys, and the involvement of the ovaries is extremely rare. The diagnosis of ovarian metastasis is made mainly by two-dimensional ultrasonography (2DUS) with color Doppler, which shows a large vessel in the center of the mass. The three-dimensional power Doppler ultrasound (3D power Doppler) and dynamic contrast-enhanced magnetic resonance imaging (MRI) are new diagnostic modalities not yet published in literature. We report a case of metastatic choriocarcinoma with left ovary involvement in a 48-year-old woman with history of molar pregnancy and irregular follow-up of this disease. We emphasize the main findings by 2DUS with color Doppler, 3D power Doppler and dynamic contrast-enhanced MRI. 3D power Doppler is able to improve the assessment of anatomical relationships of vessels with the ovarian mass, while the resonance angiography allows us to evaluate the anatomic relations of the mass and adjacent structures, as well as the iliac vessels. The 3D power Doppler and dynamic contrast-enhanced MRI are promising methods in the evaluation of metastasis arising from gestational trophoblastic tumors.

Effects of the association zidovudine plus ritonavir on the liver and kidneys of pregnant rats. Morphological and biochemical aspects.

PURPOSE: To evaluate biochemical and morphological effects on rats submitted to three different doses of the association zidovudine and ritonavir administered throughout pregnancy. METHODS: Forty pregnant EPM-1 Wistar rats weighing about 200 g were randomly divided into the control group (Ctr = drug vehicle control, n = 10) and three experimental ones which were treated with an oral solution of zidovudine/ritonavir (Exp1 = 10/20 mg/kg bw, n = 10; Exp2 = 30/60 mg/kg bw, n = 10; Exp3 = 90/180 mg/kg bw, n = 10) from 'day 0' up to the 20th day of pregnancy. At term (20th day) the rats were anesthetized. Blood and fetal and maternal organ samples (livers and kidneys) were taken for morphological and biochemical analyses. RESULTS: Upon histological examinations fetal livers and kidneys appeared normal. In contrast the maternal samples revealed structural alterations. Maternal kidneys of the three experimental groups exhibited progressive and dose-dependent histological alterations; liver alterations were detected only in Exp3. Blood levels of AST and ALT were not significantly different from the control group but urea and creatinine levels were lower in groups Exp3 and Exp1. CONCLUSIONS: The administration of zidovudine plus ritonavir throughout rat pregnancy can cause morphological as well as functional changes in maternal kidneys.

Effect of neurotrophic factor, MDP, on rats' nerve regeneration.

Our objective was to determine the immune-modulating effects of the neurotrophic factor N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) on median nerve regeneration in rats. We used male Wistar rats (120-140 days of age, weighing 250-332 g) and compared the results of three different techniques of nerve repair: 1) epineural neurorrhaphy using sutures alone (group S - 10 rats), 2) epineural neurorrhaphy using sutures plus fibrin tissue adhesive (FTA; group SF - 20 rats), and 3) sutures plus FTA, with MDP added to the FTA (group SFM - 20 rats). Functional assessments using the grasp test were performed weekly for 12 weeks to identify recovery of flexor muscle function in the fingers secondary to median nerve regeneration. Histological analysis was also utilized. The total number and diameter of myelinated fibers were determined in each proximal and distal nerve segment. Two indices, reported as percentage, were calculated from these parameters, namely, the regeneration index and the diameter change index. By the 8th week, superiority of group SFM over group S became apparent in the grasping test (P = 0.005). By the 12th week, rats that had received MDP were superior in the grasping test compared to both group S (P < 0.001) and group SF (P = 0.001). Moreover, group SF was better in the grasping test than group S (P = 0.014). However, no significant differences between groups were identified by histological analysis. In the present study, rats that had received MDP obtained better function, in the absence of any significant histological differences.

Impact of liver ex situ transection on pediatric liver transplantation.

UNLABELLED: Ex situ hepatic transection (ESHT) has allowed transplantation of younger and smaller patients than whole liver grafts. Liver transection is a technical challenge due to the prolonged back table time, possible graft lesions, and increased surgical bleeding from the cut surface. We compare the outcomes of whole versus transected liver grafts in pediatric liver transplantation. METHODS: We retrospectively studied 41 pediatric patients who underwent 42 consecutive liver transplants (1 retransplant) from cadaveric donors. The study included all patients <18 years old who were transplanted at our institution from December 2001 to September 2009. Patients were distributed into 2 groups: whole organ (WO; n = 20) and transected liver grafts (TLG; n = 21). The ESHT grafts included 17 splits and 5 reduced size livers. We evaluated the age, weight, blood component transfusions, 1-year survival, laboratory tests at 2nd and 7th days postoperatively, surgical complications, reoperations, rejection episodes, cold ischemia time, biliary reconstruction type, and donor laboratory tests. Data were analyzed using Fisher and Student's t-tests. RESULTS: The mean age was 115 months (range, 7 months to 17.6 years) in the WO group and 43.3 months (range, 5 months to 16.25 years) in the TLG group (P = .0003). Mean weight was 19.8 kg (range, 5.8-67) and 9.7 Kg (range, 5.2-57) in the WO and TLG groups, respectively (P = .0079). Red blood cell transfusion was higher in the TLG group (P = .0479). Laboratory tests showed no difference between the 2 groups considering hepatic lesions or function markers. One-year patient survivals were 90% and 85.8% among the WO and LTG, respectively (P = .588). The overall 1-year survival rate was 88.8%. CONCLUSION: ESHT allowed smaller and younger children to be transplanted. There was an increased necessity of red blood cell transfusions after hepatic transection. There was no impact on liver function or 1-year patient or graft survival after ESHT.

Dysglycemias in pregnancy: from diagnosis to treatment. Brazilian consensus statement

Há uma necessidade urgente de encontrar um consenso sobre o rastreio, diagnóstico e tratamento de todos os graus de disglicemia que podem ocorrer durante a gravidez, no Brasil, considerando-se que muitos casos de disglicemia em mulheres grávidas não está diagnosticado, levando a complicações maternas e fetais. Por esta razão a Sociedade Brasileira de Diabetes (SBD) e da Federação Brasileira de Ginecologia e Obstetrícia (FEBRASGO Sociedades), reuniram-se para apresentar esta proposta. Apresentamos aqui um consenso comum sobre a padronização da gestão clínica para mulheres grávidas com qualquer grau de disglicemia, com base em informações atuais, para melhorar a assistência médica e para evitar complicações relacionadas de disglicemia na gravidez para a mãe eo feto. Este consenso visa padronizar o diagnóstico entre clínicos gerais, endocrinologistas e obstetras, permitindo a divulgação de informações em unidades básicas de saúde, serviços públicos e privados, que são responsáveis ​​pela triagem, diagnóstico e tratamento de disglycemic pacientes grávidas.

Oral cavity is not a reservoir for Helicobacter pylori in infected patients with functional dyspepsia.

INTRODUCTION: Helicobacter pylori infection is very prevalent in Brazil, infecting almost 65% of the population. The aim of this study was to evaluate the presence of this bacterium in the oral cavity of patients with functional dyspepsia (epigastric pain syndrome), establish the main sites of infection in the mouth, and assess the frequency of cagA and vacA genotypes of oral H. pylori. METHODS: All 43 outpatients with epigastric pain syndrome, who entered the study, were submitted to upper gastrointestinal endoscopy to rule out organic diseases. Helicobacter pylori infection in the stomach was confirmed by a rapid urease test and urea breath tests. Samples of saliva, the tongue dorsum and supragingival dental plaque were collected from the oral cavity of each subject and subgingival dental plaque samples were collected from the patients with periodontitis; H. pylori infection was verified by polymerase chain reaction using primers that amplify the DNA sequence of a species-specific antigen present in all H. pylori strains; primers that amplify a region of urease gene, and primers for cagA and vacA (m1, m2, s1a, s1b, s2) genotyping. RESULTS: Thirty patients harbored H. pylori in the stomach, but it was not possible to detect H. pylori in any oral samples using P1/P2 and Urease A/B. The genotype cagA was also negative in all samples and vacA genotype could not be characterized (s-m-). CONCLUSION: The oral cavity may not be a reservoir for H. pylori in patients with epigastric pain syndrome, the bacterium being detected exclusively in the stomach.

Doppler assessment of uterine blood flow in recurrent pregnancy loss.

OBJECTIVE: To compare uterine artery pulsatility index (PI) and flow velocity wave (FVW) patterns between women with no history of abortion and women with recurrent pregnancy loss of unexplained cause. METHOD: A cross-sectional study was conducted with 43 women with recurrent pregnancy loss and 43 women with no history of abortion and at least 1 child born at term (control group). Transvaginal ultrasonography with uterine artery Doppler evaluation was performed in the second phase of the menstrual cycle to calculate the PI and analyze the FVW pattern. RESULTS: The women with recurrent pregnancy loss had a significantly higher uterine artery PI than those in the control group (2.71+/-0.54 and 2.30+/-0.44, respectively), as well as a higher incidence of FVWs of the A and B types. CONCLUSION: Compared with the control group, a higher PI and a higher incidence of FVW of the A and B types--and thus a higher uterine artery impedance--were found among women with recurrent pregnancy loss.

Venous-arterial Doppler ratios in the prediction of acidemia at birth in pregnancies with placental insufficiency.

OBJECTIVES: Investigate the prediction of birth acidemia in pregnancies with placental insufficiency using two newly created venous-arterial Doppler ratios: pulsatility index (PI) of the ductus venosus (DV) over PI of the middle cerebral artery (MCA) and PI of the DV over PI of the umbilical artery and establish cut-off values for this prediction. METHODS: This was a prospective cross-sectional study involving 47 patients with placental insufficiency managed in two Brazilian hospitals. All pregnancies were singleton, over 26 weeks of age and without structural or chromosome anomalies. A ROC curve was calculated for the venous-arterial ratios (independent variable) and acidemia (dependent variable). RESULTS: The DV/AU PI ratio was not a good predictor of acidemia at birth. The DV/MCA PI ratio was related to fetal acidemia (area under the ROC curve 0.785, p = 0.004). The cut-off value was 0.582, sensibility 66.7%, specificity 77.1% and accuracy 74.5%. CONCLUSIONS: The DV/MCA PI ratio is adequate for the diagnosis of acidemia at birth in pregnancies with placental insufficiency. The cut-off value was 0.582.

Cervical gland area as an ultrasonographic marker for preterm delivery.

OBJECTIVE: To assess the association between spontaneous preterm delivery (SPTD) in the general population and the measurement of the cervix length, cervical funneling, and absence of the cervical gland area (CGA). METHOD: A prospective cohort of 338 women carrying uncomplicated pregnancies was evaluated by transvaginal sonography between 21 and 24 weeks' gestation. RESULTS: Measurement of cervical length with less than 20 mm and the presence of cervical funneling presented a statistically significant association with SPTD before 35 weeks. The non-detection of CGA demonstrated a strong association with SPTD before 37 weeks' (p < 0.001; OR = 194.5) and before 35 weeks' gestation (p < 0.001; OR = 129.6). The multiple logistic regression analysis suggested the non-detection of CGA as the only variable to reveal statistically significance association with SPTD. CONCLUSION: The results seem to indicate that the absence of CGA can be a new and important ultrasound marker for SPTD, to be confirmed by future multicenter investigations.

True hermaphroditism-the importance of ultrasonic assessment.

Intersex states are associated with rare syndromes within a wide clinical spectrum, true hermaphroditism being the rarest of them all. It is a condition that is characterized by ovotestis, i.e. the presence of ovarian and testicular tissues in the same individual, either in separate gonads or in the same gonad. Diagnostic investigation of hermaphroditism involves ultrasound examination of the gonads, karyotype analysis and histological studies. We report the case of a 21-year-old individual with true hermaphroditism, in whom ovotestis was diagnosed on ultrasonography and which was later confirmed by anatomopathological study of the gonads. The role of ultrasound in the initial diagnostic investigation of intersex states, especially true hermaphroditism, is discussed.