UPR induces transient burst of apoptosis in islets of early lactating rats through reduced AKT phosphorylation via ATF4/CHOP stimulation of TRB3 expression

Bromati CR, Lellis-Santos C, Yamanaka TS, Nogueira TC, Leonelli M, Caperuto LC, Gorjao R, Leite AR, Anhe GF, Bordin S. UPR induces transient burst of apoptosis in islets of early lactating rats through reduced AKT phosphorylation via ATF4/CHOP stimulation of TRB3 expression. Am J Physiol Regul Integr Comp Physiol 300: R92-R100, 2011. First published November 10, 2010; doi:10.1152/ajpregu.00169.2010.-Endocrine pancreas from pregnant rats undergoes several adaptations that comprise increase in beta-cell number, mass and insulin secretion, and reduction of apoptosis. Lactogens are the main hormones that account for these changes. Maternal pancreas, however, returns to a nonpregnant state just after the delivery. The precise mechanism by which this reversal occurs is not settled but, in spite of high lactogen levels, a transient increase in apoptosis was already reported as early as the 3rd day of lactation (L3). Our results revealed that maternal islets displayed a transient increase in DNA fragmentation at L3, in parallel with decreased RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation (pAKT), a known prosurvival kinase. Wortmannin completely abolished the prosurvival action of prolactin (PRL) in cultured islets. Decreased pAKT in L3-islets correlated with increased Tribble 3 (TRB3) expression, a pseudokinase inhibitor of AKT. PERK and eIF2 alpha phosphorylation transiently increased in islets from rats at the first day after delivery, followed by an increase in immunoglobulin heavy chain-binding protein (BiP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in islets from L3 rats. Chromatin immunoprecipitation (ChIP) and Re-ChIP experiments further confirmed increased binding of the heterodimer ATF4/CHOP to the TRB3 promoter in L3 islets. Treatment with PBA, a chemical chaperone that inhibits UPR, restored pAKT levels and inhibited the increase in apoptosis found in L3. Moreover, PBA reduced CHOP and TRB3 levels in beta-cell from L3 rats. Altogether, our study collects compelling evidence that UPR underlies the physiological and transient increase in beta-cell apoptosis after delivery. The UPR is likely to counteract prosurvival actions of PRL by reducing pAKT through ATF4/CHOP-induced TRB3 expression.

MKP-1 mediates glucocorticoid-induced ERK1/2 dephosphorylation and reduction in pancreatic beta-cell proliferation in islets from early lactating mothers

Maternal pancreatic islets undergo a robust increase of mass and proliferation during pregnancy, which allows a compensation of gestational insulin resistance. Studies have described that this adaptation switches to a low proliferative status after the delivery. The mechanisms underlying this reversal are unknown, but the action of glucocorticoids (GCs) is believed to play an important role because GCs counteract the pregnancy-like effects of PRL on isolated pancreatic islets maintained in cell culture. Here, we demonstrate that ERK1/2 phosphorylation (phospho-ERK1/2) is increased in maternal rat islets isolated on the 19th day of pregnancy. Phospho-ERK1/2 status on the 3rd day after delivery (L3) rapidly turns to values lower than that found in virgin control rats (CTL). MKP-1, a protein phosphatase able to dephosphorylate ERK1/2, is increased in islets from L3 rats. Chromatin immunoprecipitation assay revealed that binding of glucocorticoid receptor (GR) to MKP-1 promoter is also increased in islets from L3 rats. In addition, dexamethasone (DEX) reduced phospho-ERK1/2 and increased MKP-1 expression in RINm5F and MIN-6 cells. Inhibition of transduction with cycloheximide and inhibition of phosphatases with orthovanadate efficiently blocked DEX-induced downregulation of phospho-ERK1/2. In addition, specific knockdown of MKP-1 with siRNA suppressed the downregulation of phosphoERK1/2 and the reduction of proliferation induced by DEX. Altogether, our results indicate that downregulation of phospho-ERK1/2 is associated with reduction in proliferation found in islets of early lactating mothers. This mechanism is probably mediated by GC-induced MKP-1 expression.

Metastatic melanoma positively influences pregnancy outcome in a mouse model: could a deadly tumor support embryo life?

The incidence of melanoma is increasing worldwide. It is one of the leading cancers in pregnancy and the most common malignancy to metastasize to placenta and fetus. There are no publications about experimental models of melanoma and pregnancy. We propose a new experimental murine model to study the effects of melanoma on pregnancy and its metastatic process. We tested several doses of melanoma cells until we arrived at the optimal dose, which produced tumor growth and allowed animal survival to the end of pregnancy. Two control groups were used: control (C) and stress control (SC) and three different routes of inoculation: intravenous (IV), intraperitoneal (IP) and subcutaneous (SC). All the fetuses and placentas were examined macroscopically and microscopically. The results suggest that melanoma is a risk factor for intrauterine growth restriction but does not affect placental weight. When inoculated by the SC route, the tumor grew only in the site of implantation. The IP route produced peritoneal tumoral growth and also ovarian and uterine metastases in 60% of the cases. The IV route produced pulmonary tumors. No placental or fetal metastases were obtained, regardless of the inoculation route. The injection of melanoma cells by any route did not increase the rate of fetal resorptions. Surprisingly, animals in the IV groups had no resorptions and a significantly higher number of fetuses. This finding may indicate that tumoral factors released in the host organism to favor tumor survival may also have a pro-gestational action and consequently improve the reproductive performance of these animals.

Effects of long-term diabetes on the structure and cell proliferation of the myometrium in the early pregnancy of mice

P>It is known that the development of diabetic complications in human pregnancy is directly related to the severity and the duration of this pathology. In this study, we developed a model of long-term type 1 diabetes to investigate its effects on the cytoarchitecture, extracellular matrix and cell proliferation during the first adaptation phase of the myometrium for pregnancy. A single dose of alloxan was used to induce diabetes in mice prior to pregnancy. To identify the temporal effects of diabetes the mice were divided into two groups: Group D1 (females that became pregnant 90-100 days after alloxan); Group D2 (females that became pregnant 100-110 days after alloxan). Uterine samples were collected after 168 h of pregnancy and processed for light and electron microscopy. In both groups the histomorphometric evaluation showed that diabetes promoted narrowing of the myometrial muscle layers which was correlated with decreased cell proliferation demonstrated by PCNA immunodetection. In D1, diabetes increased the distance between muscle layers and promoted oedema. Contrarily, in D2 the distance between muscle layers decreased and, instead of oedema, there was a markedly deposition of collagen in the myometrium. Ultrastructural analysis showed that diabetes affects the organization of the smooth muscle cells and their myofilaments. Consistently, the immunoreaction for smooth muscle alpha-actin revealed clear disorganization of the contractile apparatus in both diabetic groups. In conclusion, the present model demonstrated that long-term diabetes promotes significant alterations in the myometrium in a time-sensitive manner. Together, these alterations indicate that diabetes impairs the first phenotypic adaptation phase of the pregnant myometrium.

The Estrous Cycle Modulates Small Leucine-Rich Proteoglycans Expression in Mouse Uterine Tissues

In the pregnant mouse uterus, small leucine-rich proteoglycans (SLRPs) are drastically remodeled within a few hours after fertilization, suggesting that ovarian hormone levels modulate their synthesis and degradation. In this study, we followed by immunoperoxidase approach, the presence of four members of the SLRP family (decorin, lumican, biglycan, and fibromodulin) in the uterine tissues along the estrous cycle of the mouse. All molecules except fibromodulin, which predominates in the myometrium, showed a striking modulation in their distribution in the endometrial stroma, following the rise in the level of estrogen. Moreover, notable differences in the distribution of SLRPs were observed between superficial and deep stroma, as well as between the internal and external layers of the myometrium. Only biglycan and fibromodulin were expressed in the luminal and glandular epithelia. All four SLRPs were found in cytoplasmic granules of mononucleated cells. The pattern of distribution of the immunoreaction for these molecules in the uterine tissues was found to be estrous cycle-stage dependent, suggesting that these molecules undergo ovarian hormonal control and probably participate in the preparation of the uterus for decidualization and embryo implantation. In addition, this and previous results from our laboratory suggest the existence of two subpopulations of endometrial fibroblasts that may be related to the centrifugal development of the decidua. Anat Rec, 292:138-153, 2009. (c) 2008 Wiley-Liss, Inc.

Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton

Thyroid hormone (TH) plays a key role on post-natal bone development and metabolism, while its relevance during fetal bone development is uncertain. To Study this, pregnant once were made hypothyroid and fetuses harvested at embryonic days (E) 12.5, 14.5, 16.5 and 18.5. Despite a marked reduction in fetal tissue concentration of both T4 and T3, bone development, as assessed at the distal epiphyseal growth plate of the femur and vertebra, was largely preserved Lip to E16.5. Only at E18.5, the hypothyroid fetuses exhibited a reduction in femoral type I and type X collagen and osteocalcin mRNA levels, in the length and area of the proliferative and hypertrophic zones, in the number of chondrocytes per proliferative column, and in the number of hypertrophic chondrocyres, in addition to a slight delay in endochondral and intramembranous ossification. This Suggests that LIP to E 16.5, thyroid hormone signaling in bone is kept to a minimum. In fact, measuring the expression level of the activating and inactivating iodothyronine deiodinases (D2 and D3) helped understand how this is achieved. D3 mRNA was readily detected as early as E14.5 and its expression decreased markedly (similar to 10-fold) at E18.5, and even more at 14 days after birth (P14). In contrast. D2 mRNA expression increased significantly by E18.5 and markedly (similar to 2.5-fold) by P14. The reciprocal expression levels of D2 and D3 genes during early bone development along with the absence of a hypothyroidism-induced bone phenotype at this time Suggest that coordinated reciprocal deiodinase expression keeps thyroid hormone signaling in bone to very low levels at this early stage of bone development. (c) 2008 Elsevier Inc. All rights reserved.

A Community-based Survey of Human Toxoplasmosis in Rural Amazonia: Seroprevalence, Seroconversion Rate, and Associated Risk Factors

IgG antibodies to Toxoplasma gondii were detected in, March-April 2004, in 65.8% (95% confidence interval, 60.8-70.8%) of 342 systematically sampled subjects 5-90 years of age (87.5% of the eligible) living in a rural settlement in Amazonia, with a seroconversion rate of 9% over I year of follow-up of 99 seronegative subjects. Multiple logistic regression analysis identified age as the only significant independent predictor of seropositivity at the baseline. Each additional year of age increases the odds of being seropositive by 6%, and 76.8% of the subjects are expected to be seropositive at 30 years of age. A single high-prevalence spatial cluster, comprising 11.9% of the seropositive subjects, was detected in the area; households in the cluster were less likely to have dogs as pets and their heads had a lower education level, when compared with households located outside the cluster. The challenges for preventing human toxoplasmosis in tropical rural settings are discussed.

Bayesian Analysis for Nonlinear Regression Model Under Skewed Errors, with Application in Growth Curves

We have considered a Bayesian approach for the nonlinear regression model by replacing the normal distribution on the error term by some skewed distributions, which account for both skewness and heavy tails or skewness alone. The type of data considered in this paper concerns repeated measurements taken in time on a set of individuals. Such multiple observations on the same individual generally produce serially correlated outcomes. Thus, additionally, our model does allow for a correlation between observations made from the same individual. We have illustrated the procedure using a data set to study the growth curves of a clinic measurement of a group of pregnant women from an obstetrics clinic in Santiago, Chile. Parameter estimation and prediction were carried out using appropriate posterior simulation schemes based in Markov Chain Monte Carlo methods. Besides the deviance information criterion (DIC) and the conditional predictive ordinate (CPO), we suggest the use of proper scoring rules based on the posterior predictive distribution for comparing models. For our data set, all these criteria chose the skew-t model as the best model for the errors. These DIC and CPO criteria are also validated, for the model proposed here, through a simulation study. As a conclusion of this study, the DIC criterion is not trustful for this kind of complex model.

Childbirth self-efficacy inventory in Tanzania : a pilot study

Background. To give birth can be a stressful experience and women cope with thisstress in many different ways and have different personal outcomes. Self-efficacy orconfidence in ability to cope with labour can be considered as an important factoraffecting pregnant women’s motivation of normal childbirth and their interpretation ofthe childbirth event.The aim. The purpose of this study was to test the Chinese short form of theinstrument Childbirth self-efficacy instrument (CBSEI) in Tanzania, that measurepregnant women’s self-confidence and coping abilities during childbirth.Method. The Chinese short form of the CBSEI was used to pilot test the pregnantwomen’s confidence of childbirth to see if the questions were understood in theTanzanian culture. Besides this instrument socio-demographic data was collectedtogether with two open questions asking about attitudes and experiences of childbirth.The instrument was translated into Kiswahili. A sample of 60 pregnant women whowere visiting antenatal clinic (ANC) regularly were asked to participate and with helpfrom midwifes at two ANC places the questionnaires were filled out.Result. The result shows that the validity and reliability of the two subscales OE-16and EE-16 were established. The internal consistency reliability of the two subscaleswere high, suggesting that each of the subscale mean score provides a good overviewof self- reported belief in coping ability for childbirth.The results further show that the instrument, CBSEI in this pilot study is not able toidentify women who need extra support during childbirth.Conclusion. The reliability and validity of information presented in this pilot studysupport the use of the Chinese short form of the CBSEI as a research instrument in theTanzania culture. Further studies are recommended to get a wider understandingabout women’s coping abilities in a culture like Tanzania.

Förlossningsrädda kvinnors erfarenheter av Aurorasamtal ett till två år efter förlossning

Bakgrund: Av alla gravida kvinnor räknas omkring 5 % lida av svår förlossningsrädsla. Kvinnor med förlossningsrädsla löper högre risk för komplikationer under och efter graviditeten. I Sverige läggs idag mycket resurser på Auroraverksamhet för att hjälpa kvinnor med förlossningsrädsla. Det saknas omfattande utvärdering av Auroraverksamheten. Syfte: Syftet med detta fördjupningsarbete var att undersöka upplevelse och effekt av Aurorasamtal inför förlossning samt upplevelse av den efterföljande förlossningen bland först- och omföderskor. Metod: Studien har en retrospektiv studiedesign där datainsamling skedde via en enkätundersökning. Datamaterialet sammanställdes därefter i SPSS. Resultat: Majoriteten av kvinnorna upplevde att samtalen hjälpte dem till en mer positiv förlossningsupplevelse. Fler förstföderskor än omföderskor önskade planerat kejsarsnitt när de kom till Auroramottagningen. De flesta kvinnor som önskade vaginal förlossning blev vaginalt förlösta. Över hälften av kvinnorna som deltog i studien var mindre rädda för förlossning 1 – 2 år efter förlossningen än de upplevde att de var innan Aurorasamtalet och förlossningen. Konklusion: Aurorasamtal förefaller ha störst betydelse för omföderskor och för de kvinnor som önskar vaginal förlossning.

Internet- den nya barnmorskan? : En enkätstudie om hur gravida kvinnor söker information om graviditet och förlossning via Internet

Bakgrund: Internet används globalt inom många områden och aktuell forskning visar att gravida kvinnor använder Internet till att söka information om graviditet och förlossning. En graviditet innebär många frågor hos kvinnan och kvinnor söker efter information för att få en trygghet och försäkran om att allt är normalt med deras hälsa och barnet i magen. Syfte: Syftet är att undersöka gravida kvinnors informationssökning via Internet avseende graviditet och förlossning. Metod: Beskrivande tvärsnittstudie. Datainsamling skedde via en enkätundersökning och data analyserades med deskriptiv och jämförande ansats. Resultat: Nästan alla kvinnor i undersökningen använde Internet för att söka information om graviditet och förlossning. Kvinnorna söker information om barnets utveckling, kost/näring och graviditetslängd i hög utsträckning. Högutbildade kvinnor har andra kriterier för trovärdighet på hemsidor än kvinnor med lägre utbildning. Slutsats: Barnmorskor bör vara medvetna om gravida kvinnors användning av Internet samt själva skapa sig en uppfattning om informationen som de gravida kvinnorna läser på Internet. Vår studie visar att barnmorskors rekommendation av hemsidor på Internet har stor betydelse för gravida kvinnor.  

A conversão de D. José Brandão de Castro : a ação social de mediadores religiosos na Diocese de Propriá

This dissertation looked for to study the charisma of the religious mediator us " Movements of Christianity of Liberation " in the Diocese Sergipana of Propriá, during the decade from sixty to eighty. Centering our debate in the understanding of the social action, we have as main subject to understand the " poor " influence in the adoption of actions on the part of the mediators, in that public's favor, mainly in Fazenda Betume conflicts (1974) and of Santana dos Frades (1979). The hypotheses, we became pregnant that the mediators as D. José Brandão de Castro and the nun Maria Joana Hermínia exercised an important influence in the construction of the identity of the movements as CEBs, MEB and CPT in the area. Such influence was motivated by a conversion of the mediator D. Brandão, constituted starting from a relationship maintained between him and the members of the movements and proportionate for the critics and demands done by the popular ones. They resulted in actions in favor of the rural ones, what characterized the Church of Propriá as allied of the involved in the conflicts and no mere middleman. Before the collected material, we made use of the Analysis of Content using the poor " term " as analysis category, complemented by interviews done to members of the mentioned movements. Esta dissertação buscou estudar o carisma do mediador religioso nos “Movimentos de Cristianismo de Libertação” na Diocese Sergipana de Propriá, durante a década de sessenta a oitenta. Centrando nosso debate na compreensão da ação social, temos como questão principal entender a influência dos “pobres” na adoção de ações por parte do mediador, em favor desse público, principalmente nos conflitos da Fazenda Betume (1974) e de Santana dos Frades (1979). Como hipóteses, concebemos que os mediadores como D. José Brandão de Castro e a freira Maria Joana Hermínia exerceram uma importante influência na construção da identidade dos movimentos como as CEBs, o MEB e a CPT na região. Tal influência foi motivada por uma conversão do mediador D. Brandão, constituída a partir de uma relação mantida entre ele e os membros dos movimentos e proporcionada pelas críticas e demandas feita pelos populares. Elas resultaram em ações em favor dos campesinos, o que caracterizou a Igreja de Propriá como aliada dos envolvidos nos conflitos e não mera intermediária. Ante o material coletado, fizemos uso da Análise de Conteúdo utilizando o termo “pobre” como categoria de análise, complementada por entrevistas feitas à membros dos movimentos citados.

Gravida kvinnors tankar om amning

Internationellt sett är amningsfrekvensen i dagens Sverige hög, men har minskat något senaste åren. Studier visar att inställningen till amning är positiv, men att kvinnor upplever svårigheter i samband med amning samt en brist på information och stöd. Syftet med fördjupningsarbetet var att belysa gravida kvinnors tankar om amning, amningsinformation och stöd. Studien genomfördes med kvalitativ ansats, där data samlades in genom fokusgruppsintervjuer med 18 gravida kvinnor hösten 2012. Data bearbetades med innehållsanalys. Analysen gav ett övergripande tema; Balans mellan förväntningar och svårigheter. Fem kategorier framkom; Att vara medveten om amningens fördelar, Att vara medveten om svårigheter med amning, Att planera för sin kommande amning, Att påverkas av sin omgivning och Att ha förväntningar på stöd inför kommande amning. Resultatet visade att gravida kvinnor var medvetna om amningens fördelar och svårigheter, omgivningen påverkade deras tankar och kvinnorna ansåg ofta att amningen ”löser sig naturligt”. Tydligast framkom kvinnors känsla av bristande kunskap om amningsproblem och en önskan att få amningsinformation sent i graviditet. Amningsinformation som ges under graviditet bör vara varierad, innehållsrik och förbereda föräldrarna på att amning kan vara påfrestande. Det är viktigt att involvera partnern i information och förberedelser för amning.   Nyckelord: amning, graviditet, amningsstöd, amningsinformation, amningsproblem

”Vi gör så gott vi kan” : Vårdpersonals upplevelser av amningsstöd till gravida ochnyblivna föräldrar

Amning, amningskomplikationer, stöd och råd vid amning är en del av den sexuella och reproduktiva hälsan och ingår i barnmorskans kompetensområde.Det finns mycket forskning som beskriver nyblivna föräldrars upplevelse av amningsstöd men inte lika mycket forskning på hur vårdpersonalen upplever amningsstödet som ges till gravida och nyblivna föräldrar. Syftet med denna studie var att undersöka vårdpersonals upplevelser av amningsstöd till gravida och nyblivna föräldrar.Studien utfördes genom en kvalitativ metod utifrån en induktiv ansats. Data hämtades från intervjuer med semistrukturerade frågor i 11 fokusgrupper. All data bearbetades genom kvalitativ, induktiv innehållsanalys.Resultatet i studien visade att vårdpersonal upplever amningsstödet de ger som en viktig del i deras arbete. Amningsstödet hade brister och en betydande brist uppgavs vara kontinuiteten av amningsstöd genom hela vårdkedjan.Informanterna ansåg att amningsstödet borde förbättras och många förslag nämndes för att främja amningen hos nyblivna föräldrar och barn.Denna studie kan öka medvetenheten av den egna och kollegornas upplevelse av amningsstöd vilket kan leda till ett bättre samarbete mellan enheterna och en bättre kommunikation samt förändringar i organisationen som gynnar och främjar amningen.

The panorama and outcomes of reported pregnancies within a well defined population in rural Vietnam 1999-2004

Background Pregnancy outcomes in the general population are important public health indicators. Purpose The overall aim of this study was to investigate the outcomes of reported pregnancies within a well-defined population, to identify risk groups for adverse pregnancy outcomes, and to suggest preventive measures. Method A prospective population-based cohort study of pregnant women in Bavi district, Vietnam between 1 January 1999 and 30 June 2004. Results Pregnancy outcome was reported for 5,259 cases; 4,152 (79%) resulted in a live birth, 67 (1.3%) in a stillbirth, 733 (14%) in an induced abortion, and 282 (5.4%) in a spontaneous abortion. There was an increased risk of home delivery for women from ethnic minorities (OR?=?1.85; 95%CI?=?1.06–3.24) or with less than 6 years of schooling (OR?=?7.36; 95%CI?=?3.54–15.30). The risk of stillbirth was increased for ethnic minorities (OR?=?6.34; 95%CI?=?1.33–30.29) and women delivering at home (OR?=?6.81; 95%CI?=?2.40–19.30). The risk of induced abortion increased with maternal age. Conclusion Our findings emphasize the public health significance of access to adequate family planning, counselling, and maternal health care for all women. Policies should specifically target women from high-risk groups.