Inefficient Sox9 upregulation and absence of Rspo1 repression lead to sex reversal in the B6.XYTIR mouse gonad†.

Sry on the Y-chromosome upregulates Sox9, which in turn upregulates a set of genes such as Fgf9 to initiate testicular differentiation in the XY gonad. In the absence of Sry expression, genes such as Rspo1, Foxl2, and Runx1 support ovarian differentiation in the XX gonad. These two pathways antagonize each other to ensure the development of only one gonadal sex in normal development. In the B6.YTIR mouse, carrying the YTIR-chromosome on the B6 genetic background, Sry is expressed in a comparable manner with that in the B6.XY mouse, yet, only ovaries or ovotestes develop. We asked how testicular and ovarian differentiation pathways interact to determine the gonadal sex in the B6.YTIR mouse. Our results showed that (1) transcript levels of Sox9 were much lower than in B6.XY gonads while those of Rspo1 and Runx1 were as high as B6.XX gonads at 11.5 and 12.5 days postcoitum. (2) FOXL2-positive cells appeared in mosaic with SOX9-positive cells at 12.5 days postcoitum. (3) SOX9-positive cells formed testis cords in the central area while those disappeared to leave only FOXL2-positive cells in the poles or the entire area at 13.5 days postcoitum. (4) No difference was found at transcript levels of all genes between the left and right gonads up to 12.5 days postcoitum, although ovotestes developed much more frequently on the left than the right at 13.5 days postcoitum. These results suggest that inefficient Sox9 upregulation and the absence of Rspo1 repression prevent testicular differentiation in the B6.YTIR gonad.

Chronic exposure to polluted urban air aggravates myocardial infarction by impaired cardiac mitochondrial function and dynamics.

Air pollution exposure positively correlates with increased cardiovascular morbidity and mortality rates, mainly due to myocardial infarction (MI). Herein, we aimed to study the metabolic mechanisms underlying this association, focusing on the evaluation of cardiac mitochondrial function and dynamics, together with its impact over MI progression. An initial time course study was performed in BALB/c mice breathing filtered air (FA) or urban air (UA) in whole-body exposure chambers located in Buenos Aires City downtown for up to 16 weeks (n = 8 per group and time point). After 12 weeks, lung inflammatory cell recruitment was evident in UA-exposed mice. Interestingly, impaired redox metabolism, characterized by decreased lung SOD activity and increased GSSG levels and NOX activity, precede local inflammation in this group. At this selected time point, additional mice were exposed to FA or UA (n = 12 per group) and alveolar macrophage PM uptake and nitric oxide (NO) production was observed in UA-exposed mice, together with increased pro-inflammatory cytokine levels (TNF-α and IL-6) in BAL and plasma. Consequently, impaired heart tissue oxygen metabolism and altered mitochondrial ultrastructure and function were observed in UA-exposed mice after 12 weeks, characterized by decreased active state respiration and ATP production rates, and enhanced mitochondrial H2O2 production. Moreover, disturbed cardiac mitochondrial dynamics was detected in this group. This scenario led to a significant increase in the area of infarcted tissue following myocardial ischemia reperfusion injury in vivo, from 43 ± 3% of the area at risk in mice breathing FA to 66 ± 4% in UA-exposed mice (n = 6 per group, p < 0.01), together with a sustained increase in LVEDP during myocardial reperfusion. Taken together, our data unravel cardiac mitochondrial mechanisms that contribute to the understanding of the adverse health effects of urban air pollution exposure, and ultimately highlight the importance of considering environmental factors in the development of cardiovascular diseases.

Copper(II) and iron(III) ions inhibit respiration and increase free radical-mediated phospholipid peroxidation in rat liver mitochondria: Effect of antioxidants.

Rat liver mitochondria (1.5-2.1mg protein·mL-1) supplemented with either 25 and 100µM Cu2+ or 100 and 500µM Fe3+ show inhibition of active respiration (O2 consumption in state 3) and increased phospholipid peroxidation . Liver mitochondria were supplemented with the antioxidants reduced glutathione, N-acetylcysteine or butylated hydroxitoluene, to evaluate their effects on the above-mentioned alterations. Although the mitochondrial dysfunction is clearly associated to phospholipid peroxidation, the different responses to antioxidant supplementation indicate that the metal ions have differences in their mechanisms of toxicity. Mitochondrial phospholipid peroxidation through the formation of hydroxyl radical by a Fenton/Haber-Weiss mechanism seems to precede the respiratory inhibition and to be the main fact in Fe-induced mitochondrial dysfunction. In the case of Cu2+, it seems that the ion oxidizes glutathione, and low molecular weight protein thiol groups in a direct reaction, as part of its intracellular redox cycling. The processes involving phospholipid peroxidation, protein oxidation and mitochondrial respiratory inhibition characterize a redox dyshomeostatic situation that ultimately leads to cell death. However, Cu2+ exposure involves an additional, yet unidentified, toxic event as previous reduction of the metal with N-acetylcysteine has only a minor effect in preventing the mitochondrial damage.

WHO global survey on maternal and perinatal health in Latin America: classifying caesarean sections.

BACKGROUND: Caesarean section rates continue to increase worldwide with uncertain medical consequences. Auditing and analysing caesarean section rates and other perinatal outcomes in a reliable and continuous manner is critical for understanding reasons caesarean section changes over time. METHODS: We analyzed data on 97,095 women delivering in 120 facilities in 8 countries, collected as part of the 2004-2005 Global Survey on Maternal and Perinatal Health in Latin America. The objective of this analysis was to test if the "10-group" or "Robson" classification could help identify which groups of women are contributing most to the high caesarean section rates in Latin America, and if it could provide information useful for health care providers in monitoring and planning effective actions to reduce these rates. RESULTS: The overall rate of caesarean section was 35.4%. Women with single cephalic pregnancy at term without previous caesarean section who entered into labour spontaneously (groups 1 and 3) represented 60% of the total obstetric population. Although women with a term singleton cephalic pregnancy with a previous caesarean section (group 5) represented only 11.4% of the obstetric population, this group was the largest contributor to the overall caesarean section rate (26.7% of all the caesarean sections). The second and third largest contributors to the overall caesarean section rate were nulliparous women with single cephalic pregnancy at term either in spontaneous labour (group 1) or induced or delivered by caesarean section before labour (group 2), which were responsible for 18.3% and 15.3% of all caesarean deliveries, respectively. CONCLUSION: The 10-group classification could be easily applied to a multicountry dataset without problems of inconsistencies or misclassification. Specific groups of women were clearly identified as the main contributors to the overall caesarean section rate. This classification could help health care providers to plan practical and effective actions targeting specific groups of women to improve maternal and perinatal care.

Intracluster correlation coefficients from the 2005 WHO Global Survey on Maternal and Perinatal Health: implications for implementation research.

Cluster-based studies involving aggregate units such as hospitals or medical practices are increasingly being used in healthcare evaluation. An important characteristic of such studies is the presence of intracluster correlation, typically quantified by the intracluster correlation coefficient (ICC). Sample size calculations for cluster-based studies need to account for the ICC, or risk underestimating the sample size required to yield the desired levels of power and significance. In this article, we present values for ICCs that were obtained from data on 97,095 pregnancies and 98,072 births taking place in a representative sample of 120 hospitals in eight Latin American countries. We present ICCs for 86 variables measured on mothers and newborns from pregnancy to the time of hospital discharge, including 'process variables' representing actual medical care received for each mother and newborn. Process variables are of primary interest in the field of implementation research. We found that overall, ICCs ranged from a minimum of 0.0003 to a maximum of 0.563 (median 0.067). For maternal and newborn outcome variables, the median ICCs were 0.011 (interquartile range 0.007-0.037) and 0.054 (interquartile range 0.013-0.075) respectively; however, for process variables, the median was 0.161 (interquartile range 0.072-0.328). Thus, we confirm previous findings that process variables tend to have higher ICCs than outcome variables. We demonstrate that ICCs generally tend to increase with higher prevalences (close to 0.5). These results can help researchers calculate the required sample size for future research studies in maternal and perinatal health.

Maternal and neonatal individual risks and benefits associated with caesarean delivery: multicentre prospective study.

OBJECTIVE: To assess the risks and benefits associated with caesarean delivery compared with vaginal delivery. DESIGN: Prospective cohort study within the 2005 WHO global survey on maternal and perinatal health. SETTING: 410 health facilities in 24 areas in eight randomly selected Latin American countries; 123 were randomly selected and 120 participated and provided data PARTICIPANTS: 106,546 deliveries reported during the three month study period, with data available for 97,095 (91% coverage). MAIN OUTCOME MEASURES: Maternal, fetal, and neonatal morbidity and mortality associated with intrapartum or elective caesarean delivery, adjusted for clinical, demographic, pregnancy, and institutional characteristics. RESULTS: Women undergoing caesarean delivery had an increased risk of severe maternal morbidity compared with women undergoing vaginal delivery (odds ratio 2.0 (95% confidence interval 1.6 to 2.5) for intrapartum caesarean and 2.3 (1.7 to 3.1) for elective caesarean). The risk of antibiotic treatment after delivery for women having either type of caesarean was five times that of women having vaginal deliveries. With cephalic presentation, there was a trend towards a reduced odds ratio for fetal death with elective caesarean, after adjustment for possible confounding variables and gestational age (0.7, 0.4 to 1.0). With breech presentation, caesarean delivery had a large protective effect for fetal death. With cephalic presentation, however, independent of possible confounding variables and gestational age, intrapartum and elective caesarean increased the risk for a stay of seven or more days in neonatal intensive care (2.1 (1.8 to 2.6) and 1.9 (1.6 to 2.3), respectively) and the risk of neonatal mortality up to hospital discharge (1.7 (1.3 to 2.2) and 1.9 (1.5 to 2.6), respectively), which remained higher even after exclusion of all caesarean deliveries for fetal distress. Such increased risk was not seen for breech presentation. Lack of labour was a risk factor for a stay of seven or more days in neonatal intensive care and neonatal mortality up to hospital discharge for babies delivered by elective caesarean delivery, but rupturing of membranes may be protective. CONCLUSIONS: Caesarean delivery independently reduces overall risk in breech presentations and risk of intrapartum fetal death in cephalic presentations but increases the risk of severe maternal and neonatal morbidity and mortality in cephalic presentations.

[The contribution of violence to maternal mortality in Morelos, Mexico]. / La contribución de la violencia a la mortalidad materna en Morelos, México.

OBJECTIVE: To document the under-registration of violent deaths related to pregnancy and the importance of considering these violent deaths within the definition of maternal mortality. MATERIAL AND METHODS: The study was carried out in the state of Morelos, based on the review of all death certificates (394) of reproductive aged women (12-49 years) who died during 2001. Based on a list of diagnostic criteria we eliminated 167 certificates that were neither violent deaths nor maternal deaths. The remaining 227 certificates were further evaluated through verbal autopsy and/or review of medical charts. RESULTS: Fifty-one violent deaths were found. Eighteen maternal deaths were officially reported in 2001, however, our study identified 23 direct maternal deaths and four violent deaths during pregnancy and the post-partum period. We found that this reproductive event was the direct trigger for the homicide or suicide of these four women, and only one of these cases was documented officially. CONCLUSIONS: Violent deaths related to pregnancy should be included in official maternal mortality statistics as indirect causes of maternal deaths. This would allow for a greater and more accurate understanding of violent maternal deaths and guide appropriate prevention and care policies, programs and services. Verbal autopsy is a useful technique for identifying cases of violent maternal deaths.

Caesarean delivery rates and pregnancy outcomes: the 2005 WHO global survey on maternal and perinatal health in Latin America.

BACKGROUND: Caesarean delivery rates continue to increase worldwide. Our aim was to assess the association between caesarean delivery and pregnancy outcome at the institutional level, adjusting for the pregnant population and institutional characteristics. METHODS: For the 2005 WHO global survey on maternal and perinatal health, we assessed a multistage stratified sample, comprising 24 geographic regions in eight countries in Latin America. We obtained individual data for all women admitted for delivery over 3 months to 120 institutions randomly selected from of 410 identified institutions. We also obtained institutional-level data. FINDINGS: We obtained data for 97,095 of 106,546 deliveries (91% coverage). The median rate of caesarean delivery was 33% (quartile range 24-43), with the highest rates of caesarean delivery noted in private hospitals (51%, 43-57). Institution-specific rates of caesarean delivery were affected by primiparity, previous caesarean delivery, and institutional complexity. Rate of caesarean delivery was positively associated with postpartum antibiotic treatment and severe maternal morbidity and mortality, even after adjustment for risk factors. Increase in the rate of caesarean delivery was associated with an increase in fetal mortality rates and higher numbers of babies admitted to intensive care for 7 days or longer even after adjustment for preterm delivery. Rates of preterm delivery and neonatal mortality both rose at rates of caesarean delivery of between 10% and 20%. INTERPRETATION: High rates of caesarean delivery do not necessarily indicate better perinatal care and can be associated with harm.

La contribución de la violencia a la mortalidad materna en Morelos, México / The contribution of violence to maternal mortality in Morelos, Mexico

OBJETIVO: Documentar el subregistro de muertes violentas relacionadas con el embarazo y la importancia de considerar, dentro de la definición de mortalidad materna, aquellas muertes producidas también por causas relacionadas con violencia. MATERIAL Y MÉTODOS: El estudio se realizó en el estado de Morelos, a partir de 394 certificados de defunción de mujeres entre 12 y 49 años de edad que murieron a lo largo del año 2001. Con base en una lista de diagnósticos de los certificados de defunción, se excluyeron 167 casos que, por las causas de muerte determinadas en el certificado de defunción, no se consideraron que podrían haber sido muertes maternas ni muertes violentas. Posteriormente se realizó el análisis de los 227 certificados restantes a través de la revisión de expedientes clínicos y/o autopsias verbales. RESULTADOS: Se encontraron 51 muertes violentas. Las estadísticas oficiales señalan que en 2001 hubo 18 muertes maternas, mientras que este estudio identificó 23 muertas maternas directas más cuatro muertas violentas durante el embarazo y el posparto. Es decir, se encontró que el evento reproductivo fue el factor que desencadenó el homicidio o suicidio de cuatro mujeres. Excepto en un caso, este hecho no está señalado ni relacionado en los registros oficiales. CONCLUSIONES: Se recomienda la inclusión de la violencia relacionada con la reproducción en los registros oficiales de mortalidad materna como una causa indirecta. Esto permitiría profundizar la comprensión de las causas de la mortalidad materna y orientaría la elaboración de políticas, programas y servicios de prevención y atención. La autopsia verbal (AV) es una técnica que ayuda a la identificación de casos de embarazo y muertes maternas violentas.

OBJECTIVE: To document the under-registration of violent deaths related to pregnancy and the importance of considering these violent deaths within the definition of maternal mortality. MATERIAL AND METHODS: The study was carried out in the state of Morelos, based on the review of all death certificates (394) of reproductive aged women (12-49 years) who died during 2001. Based on a list of diagnostic criteria we eliminated 167 certificates that were neither violent deaths nor maternal deaths. The remaining 227 certificates were further evaluated through verbal autopsy and/or review of medical charts. RESULTS: Fifty-one violent deaths were found. Eighteen maternal deaths were officially reported in 2001, however, our study identified 23 direct maternal deaths and four violent deaths during pregnancy and the post-partum period. We found that this reproductive event was the direct trigger for the homicide or suicide of these four women, and only one of these cases was documented officially. CONCLUSIONS: Violent deaths related to pregnancy should be included in official maternal mortality statistics as indirect causes of maternal deaths. This would allow for a greater and more accurate understanding of violent maternal deaths and guide appropriate prevention and care policies, programs and services. Verbal autopsy is a useful technique for identifying cases of violent maternal deaths.

Deaths from complications of unsafe abortion: misclassified second trimester deaths.

This study measured the contribution of abortion-related deaths to overall maternal mortality and calculated the underestimation of maternal mortality using verbal autopsy and clinical record review where available. We reviewed 807 death certificates of women aged 12-50 who died in 2001 in two sites of about 1.5 million inhabitants each in the state of Morelos (primarily rural) and the municipality of Nezahualcóyotl (primarily urban) in the state of Mexico. Deaths were classified as definite, possible or non-maternal deaths. Finally we identified abortion-related deaths and calculated the underestimation of maternal mortality. Among 326 possible maternal deaths, we encountered five misclassified cases: one spontaneous abortion and four non-abortion maternal deaths. Among 32 registered maternal deaths, we found four misclassified cases that were actually second trimester, abortion-related deaths. There were no officially registered abortion-related deaths in either Morelos or Nezahualcóyotl, making the overall underestimation of abortion mortality 100%. Abortion contributed 13.5% of all maternal deaths. The overall underestimation of maternal mortality was 13.55%, higher in Morelos (21.7%). There were no unregistered maternal deaths in Nezahualcóyotl. Unsafe abortion continues to be an important cause of maternal mortality, though first trimester deaths appear to be decreasing. We identified domestic violence as an important cause of death among pregnant and post-partum women, and two abortion-related suicides, and believe these should be reconsidered as indirect maternal deaths. The misclassification of second trimester abortion deaths as maternal deaths from other causes is an obstacle to preventing them.