Toxicity and effectiveness of carboplatin in obese or overweight patients.

OBJECTIVE: To evaluate the efficiency and toxicity of carboplatin using actual body weight in obese/overweight patients using the Calvert formula with Cockcroft-Gault for CrCl estimation. METHODS: We evaluated the association of BMI in regards to efficiency and toxicity in a retrospective cohort study of patients who started treatment with carboplatin between 2012 and 2013. Cohorts included obese/overweight patients and normal-weight patients. Efficiency was measured by overall survival, progression-free survival and response rate. Toxicity was measured by the proportion of dose reductions and delays of chemotherapy cycles. We utilized a bivariate and multivariate analysis. RESULTS: Eighty-six patients were included in the study (50% obese/overweight). There was not a statistically significant difference in effectiveness and toxicity between the two groups in BMI. In the multivariate analysis, BMI not was associated with overall survival (hazard ratio: 0.95, 95% CI: 0.54-1.66, p = 0.849), progression-free survival (hazard ratio: 0.91; 95% CI: 0.54-1.54; p = 0.732), cycle delays (odds ratio (OR): 1.47, 95% CI: 0.80-2.69, p = 0.218) or carboplatin dose reductions (OR: 0.87, 95% CI: 0.35-2.15, p = 0.760). Response rate was 53.5% in both groups. CONCLUSIONS: In our study, obese and overweight cancer patients did not show a statistically significant difference in terms of effectiveness and toxicity compared to normal-weight cancer patients who were treated with carboplatin using their actual body weight with the Calvert formula and Cockcroft-Gault for CrCl estimation. Therefore, it was appropriate to use the actual body weight for our patients.

Overexpression of the short endoglin isoform reduces renal fibrosis and inflammation after unilateral ureteral obstruction.

Transforming growth factor beta 1 (TGF-ß1) is one of the most studied cytokines involved in renal tubulo-interstitial fibrosis, which is characterized by myofibroblast abundance and proliferation, and high buildup of extracellular matrix in the tubular interstitium leading to organ failure. Endoglin (Eng) is a 180-kDa homodimeric transmembrane protein that regulates a great number of TGF-ß1 actions in different biological processes, including ECM synthesis. High levels of Eng have been observed in experimental models of renal fibrosis or in biopsies from patients with chronic kidney disease. In humans and mice, two Eng isoforms are generated by alternative splicing, L-Eng and S-Eng that differ in the length and composition of their cytoplasmic domains. We have previously described that L-Eng overexpression promotes renal fibrosis after unilateral ureteral obstruction (UUO). However, the role of S-Eng in renal fibrosis is unknown and its study would let us analyze the possible function of the cytoplasmic domain of Eng in this process. For this purpose, we have generated a mice strain that overexpresses S-Eng (S-ENG(+)) and we have performed an UUO in S-ENG(+) and their wild type (WT) control mice. Our results indicate that obstructed kidney of S-ENG(+) mice shows lower levels of tubulo-interstitial fibrosis, less inflammation and less interstitial cell proliferation than WT littermates. Moreover, S-ENG(+) mice show less activation of Smad1 and Smad2/3 pathways. Thus, S-Eng overexpression reduces UUO-induced renal fibrosis and some associated mechanisms. As L-Eng overexpression provokes renal fibrosis we conclude that Eng-mediated induction of renal fibrosis in this model is dependent on its cytoplasmic domain.

Absence of K-Ras Reduces Proliferation and Migration But Increases Extracellular Matrix Synthesis in Fibroblasts.

The involvement of Ras-GTPases in the development of renal fibrosis has been addressed in the last decade. We have previously shown that H- and N-Ras isoforms participate in the regulation of fibrosis. Herein, we assessed the role of K-Ras in cellular processes involved in the development of fibrosis: proliferation, migration, and extracellular matrix (ECM) proteins synthesis. K-Ras knockout (KO) mouse embryonic fibroblasts (K-ras(-/-) ) stimulated with transforming growth factor-ß1 (TGF-ß1) exhibited reduced proliferation and impaired mobility than wild-type fibroblasts. Moreover, an increase on ECM production was observed in K-Ras KO fibroblasts in basal conditions. The absence of K-Ras was accompanied by reduced Ras activation and ERK phosphorylation, and increased AKT phosphorylation, but no differences were observed in TGF-ß1-induced Smad signaling. The MEK inhibitor U0126 decreased cell proliferation independently of the presence of K-ras but reduced migration and ECM proteins expression only in wild-type fibroblasts, while the PI3K-AKT inhibitor LY294002 decreased cell proliferation, migration, and ECM synthesis in both types of fibroblasts. Thus, our data unveil that K-Ras and its downstream effector pathways distinctively regulate key biological processes in the development of fibrosis. Moreover, we show that K-Ras may be a crucial mediator in TGF-ß1-mediated effects in this cell type. J. Cell. Physiol. 231: 2224-2235, 2016. © 2016 Wiley Periodicals, Inc.

Maternal near miss and predictive ability of potentially life-threatening conditions at selected maternity hospitals in Latin America.

BACKGROUND: Every year millions of women around the world suffer from pregnancy, childbirth and postpartum complications. Women who survive the most serious clinical conditions are regarded as to have experienced a severe acute maternal complication called maternal near miss (MNM). Information about MNM cases may complement the data collected through the analysis of maternal death, and was proposed as a helpful tool to identify strengths and weaknesses of health systems in relation to maternal health care. The purpose of this study is to evaluate the performance of a systematized form to detect severe maternal outcomes (SMO) in 20 selected maternity hospitals from Latin America (LAC). METHODS: Cross-sectional study. Data were obtained from analysis of hospital records for all women giving birth and all women who had a SMO in the selected hospitals. Univariate and multivariate adjusted logistic regression models were used to assess the predictive ability of different conditions to identify SMO cases. In parallel, external auditors were hired for reviewing and reporting the total number of discharges during the study period, in order to verify whether health professionals at health facilities identified all MNM and Potentially life-threatening condition (PLTC) cases. RESULTS: Twenty hospitals from twelve LAC were initially included in the study and based on the level of coverage, 11 hospitals with a total of 3,196records were included for the final analysis. The incidence of SMO and MNM outcomes was 12.9 and 12.3 per 1,000 live births, respectively. The ratio of MNM to maternal death was 19 to 1, with a mortality index of 5.1 %. Both univariate and multivariate analysis showed a good performance for a number of clinical and laboratory conditions to predict a severe maternal outcome, however, their clinical relevance remains to be confirmed. Coherence between health professionals and external auditors to identify SMO was high (around 100 %). CONCLUSIONS: The form tested, was well accepted by health professionals and was capable of identifying 100 % of MNM cases and more than 99 % of PLTC variables. Altered state of consciousness, oliguria, placenta accrete, pulmonary edema, and admission to Intensive Care Unit have a high (LR+ ≥80) capacity to anticipate a SMO.

Outcomes of non-vertex second twins, following vertex vaginal delivery of first twin: a secondary analysis of the WHO Global Survey on maternal and perinatal health.

BACKGROUND: Mode of delivery remains a topic of debate in vertex/non-vertex twin pregnancies. We used the WHO Global Survey dataset to determine the risk of adverse maternal/perinatal outcomes associated with presentation of the second twin, following vaginal delivery of a vertex first twin. METHODS: We analysed a derived dataset of twin pregnancies ≥ 32 weeks gestation where the first twin was vertex and delivered vaginally. Maternal, delivery and neonatal characteristics and adverse outcomes were reported by presentation of the second twin. Logistic regression models (adjusted for maternal and perinatal confounders, mode of delivery and region) were developed to determine odds of adverse outcomes associated with presentation. RESULTS: 1,424 twin pregnancies were included, 25.9% of these had a non-vertex second twin and Caesarean was more common in non-vertex presentations (6.2% vs 0.9%, p < 0.001). While the odds of Apgar < 7 at 5 minutes were higher in non-vertex presenting second twins (16.0% vs 11.4%, AOR 1.42 95% CI 1.01-2.00), the odds of maternal ICU admission (4.6% vs 1.7%, AOR 1.30, 95% CI 0.88-1.94), blood transfusion (6.0% vs 3.4%, AOR 1.23, 95% CI 0.67-2.25), stillbirth (7.6% vs 4.7%, AOR 1.15, 95% CI 0.72-1.73), early neonatal death (3.8% vs 2.1%, AOR 1.68, 95% CI 0.96-2.94), and NICU admission (26.6% vs 23.2%, AOR 0.93, 95% CI 0.62-1.39) were not. CONCLUSION: After a vaginal delivery of a vertex first twin, non-vertex presentation of the second twin is associated with increased odds of Apgar <7 at 5 minutes, but not of other maternal/perinatal outcomes. Presentation of the second twin is not as important a consideration in planning twin vaginal birth as previously considered.

Infection-related severe maternal outcomes and case fatality rates in 43 low and middle-income countries across the WHO regions: Results from the Global Maternal Sepsis Study (GLOSS).

The highest toll of maternal mortality due to infections is reported in low and middle-income countries (LMICs). However, more evidence is needed to understand the differences in infection-related severe maternal outcomes (SMO) and fatality rates across the WHO regions. This study aimed to compare the burden of infection-related SMO and case fatality rates across the WHO regions using the Global Maternal Sepsis Study (GLOSS) data. GLOSS was a hospital-based one-week inception prospective cohort study of pregnant or recently pregnant women admitted with suspected or confirmed infection in 2017. Four hundred and eight (408) hospitals from 43 LMICs in the six WHO regions were considered in this analysis. We used a logistic regression model to compare the odds of infection-related SMOs by region. We then calculated the fatality rate as the proportion of deaths over the total number of SMOs, defined as maternal deaths and near-misses. The proportion of SMO was 19.6% (n = 141) in Africa, compared to 18%(n = 22), 15.9%(n = 50), 14.7%(n = 48), 12.1%(n = 95), and 10.8%(n = 21) in the Western Pacific, European, Eastern Meditteranean, Americas, and South-Eastern Asian regions, respectively. Women in Africa were more likely to experience SMO than those in the Americas (aOR = 2.41, 95%CI: [1.78 to 2.83]), in South-East Asia (aOR = 2.60, 95%CI: [1.57 to 4.32]), and the Eastern Mediterranean region (aOR = 1.58, 95%CI: [1.08 to 2.32]). The case fatality rate was 14.3%[3.05% to 36.34%] (n/N = 3/21) and 11.4%[6.63% to 17.77%] (n/N = 16/141) in the South-East Asia and Africa, respectively. Infection-related SMOs and case fatality rates were highest in Africa and Southeast Asia. Specific attention and actions are needed to prevent infection-related maternal deaths and severe morbidity in these two regions.

Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma.

The impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of KRASG12D-driven lung adenocarcinoma (LUAD). SOS2 ablation shows some protection during early stages but only SOS1 ablation causes significant, specific long term increase of survival/lifespan of the KRASG12D mice associated to markedly reduced tumor burden and reduced populations of cancer-associated fibroblasts, macrophages and T-lymphocytes in the lung tumor microenvironment (TME). SOS1 ablation also causes specific shrinkage and regression of LUAD tumoral masses and components of the TME in pre-established KRASG12D LUAD tumors. The critical requirement of SOS1 for KRASG12D-driven LUAD is further confirmed by means of intravenous tail injection of KRASG12D tumor cells into SOS1KO/KRASWT mice, or of SOS1-less, KRASG12D tumor cells into wildtype mice. In silico analyses of human lung cancer databases support also the dominant role of SOS1 regarding tumor development and survival in LUAD patients. Our data indicate that SOS1 is critically required for development of KRASG12D-driven LUAD and confirm the validity of this RAS-GEF activator as an actionable therapeutic target in KRAS mutant LUAD.

Urinary KIM-1 Correlates with the Subclinical Sequelae of Tubular Damage Persisting after the Apparent Functional Recovery from Intrinsic Acute Kidney Injury.

Acute kidney injury (AKI) poses an increased risk factor for new AKI episodes, progression to chronic kidney disease, and death. A worsened evolution has been linked to an incomplete renal repair beyond the apparent functional recovery based on plasma creatinine (pCr) normalization. However, structural sequelae pass largely unnoticed due to the absence of specific diagnostic tools. The urinary kidney injury molecule 1 (KIM-1) participates in renal tissue damage and repair and is proposed as a biomarker of early and subclinical AKI. Thus, we study in this paper the evolution of KIM-1 urinary excretion alongside renal tissue sequelae after an intrinsic AKI episode induced by cisplatin in Wistar rats. Creatinine clearance, pCr, proteinuria and the fractional excretion of Na+ and glucose were used to monitor renal function. Renal tissue damage was blindly scored in kidney specimens stained with hematoxylin-eosin and periodic acid-Schiff. KIM-1 urinary excretion and renal mRNA expression were also assessed. Finally, we analyzed urinary KIM-1 in patients apparently recovered from AKI. Our results show that, after the normalization of the standard markers of glomerular filtration and tubular function, the extent of persistent histological findings of tissue repair correlates with the renal expression and urinary level of KIM-1 in rats. In addition, KIM-1 is also elevated in the urine of a significant fraction of patients apparently recovered from an AKI. Besides its potential utility in the early and subclinical diagnosis of renal damage, this study suggests a new application of urinary KIM-1 in the non-invasive follow-up of renal repair after AKI.

The Importance of Being PI3K in the RAS Signaling Network.

Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. Ras-driven cancers are usually aggressive and difficult to treat. Although the recent Food and Drug Administration (FDA) approval of the first Ras G12C inhibitor is an important milestone, only a small percentage of patients will benefit from it. A better understanding of the context in which Ras operates in different tumor types and the outcomes mediated by each effector pathway may help to identify additional strategies and targets to treat Ras-driven tumors. Evidence emerging in recent years suggests that both oncogenic Ras signaling in tumor cells and non-oncogenic Ras signaling in stromal cells play an essential role in cancer. PI3K is one of the main Ras effectors, regulating important cellular processes such as cell viability or resistance to therapy or angiogenesis upon oncogenic Ras activation. In this review, we will summarize recent advances in the understanding of Ras-dependent activation of PI3K both in physiological conditions and cancer, with a focus on how this signaling pathway contributes to the formation of a tumor stroma that promotes tumor cell proliferation, migration, and spread.

Biomarkers of persistent renal vulnerability after acute kidney injury recovery.

Acute kidney injury (AKI) is a risk factor for new AKI episodes, chronic kidney disease, cardiovascular events and death, as renal repair may be deficient and maladaptive, and activate proinflammatory and profibrotic signals. AKI and AKI recovery definitions are based on changes in plasma creatinine, a parameter mostly associated to glomerular filtration, but largely uncoupled from renal tissue damage. The evolution of structural and functional repair has been incompletely described. We thus aimed at identifying subclinical sequelae persisting after recovery from cisplatin-induced AKI in rats. Compared to controls, after plasma creatinine recovery, post-AKI kidneys showed histological alterations and attendant susceptibility to new AKI episodes. Tubular function (assessed by the furosemide stress test, FST) also remained affected. Lingering parenchymal and functional subclinical alterations were paralleled by tapering, but abnormally high levels of urinary albumin, transferrin, insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases-2 (TIMP-2) and, especially, the [TIMP-2]*[IGFBP7] product. As subclinical surrogates of incomplete renal recovery, the FST and the urinary [TIMP-2]*[IGFBP7] product provide two potential diagnostic tools to monitor the sequelae and kidney vulnerability after the apparent recovery from AKI.

Availability of facility resources and services and infection-related maternal outcomes in the WHO Global Maternal Sepsis Study: a cross-sectional study.

BACKGROUND: Infections are among the leading causes of maternal mortality and morbidity. The Global Maternal Sepsis and Neonatal Initiative, launched in 2016 by WHO and partners, sought to reduce the burden of maternal infections and sepsis and was the basis upon which the Global Maternal Sepsis Study (GLOSS) was implemented in 2017. In this Article, we aimed to describe the availability of facility resources and services and to analyse their association with maternal outcomes. METHODS: GLOSS was a facility-based, prospective, 1-week inception cohort study implemented in 713 health-care facilities in 52 countries and included 2850 hospitalised pregnant or recently pregnant women with suspected or confirmed infections. All women admitted for or in hospital with suspected or confirmed infections during pregnancy, childbirth, post partum, or post abortion at any of the participating facilities between Nov 28 and Dec 4 were eligible for inclusion. In this study, we included all GLOSS participating facilities that collected facility-level data (446 of 713 facilities). We used data obtained from individual forms completed for each enrolled woman and their newborn babies by trained researchers who checked the medical records and from facility forms completed by hospital administrators for each participating facility. We described facilities according to country income level, compliance with providing core clinical interventions and services according to women's needs and reported availability, and severity of infection-related maternal outcomes. We used a logistic multilevel mixed model for assessing the association between facility characteristics and infection-related maternal outcomes. FINDINGS: We included 446 facilities from 46 countries that enrolled 2560 women. We found a high availability of most services and resources needed for obstetric care and infection prevention. We found increased odds for severe maternal outcomes among women enrolled during the post-partum or post-abortion period from facilities located in low-income countries (adjusted odds ratio 1·84 [95% CI 1·05-3·22]) and among women enrolled during pregnancy or childbirth from non-urban facilities (adjusted odds ratio 2·44 [1·02-5·85]). Despite compliance being high overall, it was low with regards to measuring respiratory rate (85 [24%] of 355 facilities) and measuring pulse oximetry (184 [57%] of 325 facilities). INTERPRETATION: While health-care facilities caring for pregnant and recently pregnant women with suspected or confirmed infections have access to a wide range of resources and interventions, worse maternal outcomes are seen among recently pregnant women located in low-income countries than among those in higher-income countries; this trend is similar for pregnant women. Compliance with cost-effective clinical practices and timely care of women with particular individual characteristics can potentially improve infection-related maternal outcomes. FUNDING: UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO, Merck for Mothers, and US Agency for International Development.

Course of serological tests in treated subjects with chronic Trypanosoma cruzi infection: A systematic review and meta-analysis of individual participant data.

OBJECTIVE: To determine the course of serological tests in subjects with chronic Trypanosoma cruzi infection treated with anti-trypanosomal drugs. METHODS: A systematic review and meta-analysis was conducted using individual participant data. Survival analysis and the Cox proportional hazards regression model with random effects to adjust for covariates were applied. The protocol was registered in the PROSPERO database (http://www.crd.york.ac.uk/PROSPERO; CRD42012002162). RESULTS: A total of 27 studies (1296 subjects) conducted in eight countries were included. The risk of bias was low for all domains in 17 studies (63.0%). Nine hundred and thirteen subjects were assessed (149 seroreversion events, 83.7% censored data) for enzyme-linked immunosorbent assay (ELISA), 670 subjects (134 events, 80.0% censored) for indirect immunofluorescence assay (IIF), and 548 subjects (99 events, 82.0% censored) for indirect hemagglutination assay (IHA). A higher probability of seroreversion was observed within a shorter time span in subjects aged 1-19 years compared to adults. The chance of seroreversion also varied according to the country where the infection might have been acquired. For instance, the pooled adjusted hazard ratio between children/adolescents and adults for the IIF test was 1.54 (95% confidence interval 0.64-3.71) for certain countries of South America (Argentina, Bolivia, Chile, and Paraguay) and 9.37 (95% confidence interval 3.44-25.50) for Brazil. CONCLUSIONS: The disappearance of anti-T. cruzi antibodies was demonstrated along the course of follow-up. An interaction between age at treatment and country setting was found.

Identification of bone morphogenetic protein 9 (BMP9) as a novel profibrotic factor in vitro.

Upregulated synthesis of extracellular matrix (ECM) proteins by myofibroblasts is a common phenomenon in the development of fibrosis. Although the role of TGF-ß in fibrosis development has been extensively studied, the involvement of other members of this superfamily of cytokines, the bone morphogenetic proteins (BMPs) in organ fibrosis has given contradictory results. BMP9 is the main ligand for activin receptor-like kinase-1 (ALK1) TGF-ß1 type I receptor and its effect on fibrosis development is unknown. Our purpose was to study the effect of BMP9 in ECM protein synthesis in fibroblasts, as well as the involved receptors and signaling pathways. In cultured mice fibroblasts, BMP9 induces an increase in collagen, fibronectin and connective tissue growth factor expression, associated with Smad1/5/8, Smad2/3 and Erk1/2 activation. ALK5 inhibition with SB431542 or ALK1/2/3/6 with dorsomorphin-1, inhibition of Smad3 activation with SIS3, and inhibition of the MAPK/Erk1/2 with U0126, demonstrates the involvement of these pathways in BMP9-induced ECM synthesis in MEFs. Whereas BMP9 induced Smad1/5/8 phosphorylation through ALK1, it also induces Smad2/3 phosphorylation through ALK5 but only in the presence of ALK1. Summarizing, this is the first study that accurately identifies BMP9 as a profibrotic factor in fibroblasts that promotes ECM protein expression through ALK1 and ALK5 receptors.

Course of Chronic Trypanosoma cruzi Infection after Treatment Based on Parasitological and Serological Tests: A Systematic Review of Follow-Up Studies.

BACKGROUND: Chagas disease is caused by the flagellate protozoan Trypanosoma cruzi (T. cruzi). It is endemic in Latin American countries outside the Caribbean. The current criterion for cure in the chronic phase of the disease is the negativization of at least two serological tests such as enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence assay (IIF) and indirect hemagglutination assay (IHA). The serological evolution of treated subjects with chronic T. cruzi infection is variable. Treatment failure is indicated by a positive parasitological and/or molecular test (persistence of parasitemia). OBJECTIVES: To summarize the pattern of response to treatment of parasitological, molecular and serological tests performed during the follow-up of subjects with chronic T. cruzi infection. METHODS: Electronic searches in relevant databases and screening of citations of potentially eligible articles were accomplished. Organizations focusing on neglected infectious diseases were asked for help in identifying relevant studies. Included studies were randomized controlled trials (RCTs), quasi-RCTs, and cohort studies involving adults and children with chronic infection who received trypanocidal treatment (benznidazole or nifurtimox) and were followed over time. The assessment of risk of bias was performed separately for each study design. The Cochrane Collaboration's tool and the guidelines developed by Hayden et al. were used. Two reviewers extracted all data independently. A third review author was consulted in case of discordant opinion. Additional analyses were defined in ad-hoc basis. Scatter plots for percentage of positive parasitological and molecular tests and for negative serological tests were developed by using the lowess curve technique. Heterogeneity was measured by I2. The protocol was registered in PROSPERO, an international prospective register of systematic review protocols (Registration Number CRD42012002162). RESULTS: Out of 2,136 citations screened, 54 studies (six RCTs and 48 cohort studies) were included. The smoothed curves for positive xenodiagnosis and positive polymerase chain reaction (PCR) were characterized by a sharp decrease at twelve month posttreatment. Afterwards, they reached 10-20% and 40% for xenodiagnosis and PCR, respectively. The smoothed curves for negative conventional serological tests increased up to 10% after 48 months of treatment. In the long-term, the rate of negativization was between 20% and 45%. The main sources of bias identified across cohort studies were the lack of control for confounding and attrition bias. In general, RCTs were judged as low risk of bias in all domains. The level of heterogeneity across included studies was moderate to high. Additional analysis were incomplete because of the limited availability of data. In this regard, the country of origin of study participants might affect the results of parasitological and molecular tests, while the level of risk of bias might affect serological outcomes. Subgroup analysis suggested that seronegativization occurs earlier in children compared to adults. CONCLUSIONS: We acknowledge that there is a dynamic pattern of response based on parasitological, molecular and serological tests in subjects chronically infected with T. cruzi after treatment. Our findings suggest a trypanocidal effect in the long-term follow-up. Further research is needed to explore potential sources of heterogeneity and to conduct reliable subgroup analysis.

Accuracy of angiogenic biomarkers at ⩽20weeks' gestation in predicting the risk of pre-eclampsia: A WHO multicentre study.

OBJECTIVE: To assess the accuracy of angiogenic biomarkers to predict pre-eclampsia. DESIGN: Prospective multicentre study. From 2006 to 2009, 5121 pregnant women with risk factors for pre-eclampsia (nulliparity, diabetes, previous pre-eclampsia, chronic hypertension) from Argentina, Colombia, Peru, India, Italy, Kenya, Switzerland and Thailand had their serum tested for sFlt-1, PlGF and sEng levels and their urine for PlGF levels at ⩽20, 23-27 and 32-35weeks' gestation (index tests, results blinded from carers). Women were monitored for signs of pre-eclampsia, diagnosed by systolic blood pressure ⩾140mmHg and/or diastolic blood pressure ⩾90mmHg, and proteinuria (protein/creatinine ratio ⩾0.3, protein ⩾1g/l, or one dipstick measurement ⩾2+) appearing after 20weeks' gestation. Early pre-eclampsia was defined when these signs appeared ⩽34weeks' gestation. MAIN OUTCOME MEASURE: Pre-eclampsia. RESULTS: Pre-eclampsia was diagnosed in 198 of 5121 women tested (3.9%) of whom 47 (0.9%) developed it early. The median maternal serum concentrations of index tests were significantly altered in women who subsequently developed pre-eclampsia than in those who did not. However, the area under receiver operating characteristics curve at ⩽20weeks' gestation were closer to 0.5 than to 1.0 for all biomarkers both for predicting any pre-eclampsia or at ⩽34weeks' gestation. The corresponding sensitivity, specificity and likelihood ratios were poor. Multivariable models combining sEng with clinical features slightly improved the prediction capability. CONCLUSIONS: Angiogenic biomarkers in first half of pregnancy do not perform well enough in predicting the later development of pre-eclampsia.

Effectiveness of a brief primary care intervention to reduce passive smoking in babies: a cluster randomised clinical trial.

BACKGROUND: Tobacco smoke pollution (TSP) has major negative effects on infant health. Our objectives were to determine the effectiveness of a brief primary care intervention directed at parents who smoke in reducing babies' TSP exposure, and to establish variables related to greater exposure. METHOD: A multicentre, open, cluster-randomised clinical trial in Catalonia. The 83 participating primary health paediatric teams of the Catalan Health Service recruited 1101 babies whose parents were smokers. The intervention group (IG) received a brief TSP intervention; the control group (CG) received the usual care. Outcomes were measured by parents' reported strategies to avoid TSP exposure. Baseline clinical data and characteristics of each baby's TSP exposure were collected, along with infant hair samples and parents' tobacco use and related attitudes/behaviours. At 3-month and 6-month follow-up, behavioural changes to avoid TSP exposure were recorded; the association between reported parental behaviours and nicotine concentration in infant hair samples was tested in a random sample of 253 babies at baseline and 6 months. RESULTS: During follow-up, TSP-avoidance strategies improved more in the IG than in the CG: 35.4% and 26.9% ( p=0.006) at home, and 62.2% and 53.1% in cars (p=0.008). Logistic regression showed adjusted ORs for appropriate measures in the IG versus CG of 1.59 (95% CI 1.21 to 2.09) at home and 1.30 (95% CI 0.97 to 1.75) in cars. Hair samples showed that 78.7% of the babies tested were exposed. Reduced nicotine concentration was associated with improved implementation of effective strategies reported by parents at home (p=0.029) and in cars (p=0.014). CONCLUSIONS: The intervention produced behavioural changes to avoid TSP exposure in babies. The proportion of babies with nicotine (>=1ng/mg) in hair samples at baseline is a concern. TRIAL REGISTRATION NUMBER: Clinical Trials.gov Identifier: NCT00788996.

Role of 5-HT7 receptors in the inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats.

The role of calcitonin gene-related peptide (CGRP) in the modulation of vascular tone has been widely documented. Indeed, electrical stimulation of the perivascular sensory outflow in pithed rats induces vasodepressor responses by activation of CGRP receptors. This study investigated the role of 5-HT7 receptors in the inhibition of the rat vasodepressor sensory outflow. Male Wistar pithed rats were pretreated with i.v. continuous infusions of hexamethonium and methoxamine, followed by physiological saline or AS-19 (a 5-HT7 receptor agonist). Then, electrical stimulation of the spinal cord resulted in frequency-dependent decreases in DBP. The infusions of AS-19, as compared to those of saline, inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i.v. bolus injections of exogenous α-CGRP. This inhibition by AS-19 was abolished by the antagonists pimozide (5-HT7) or sulfisoxazole (ETA), but not by indomethacin (COX1/2) or losartan (AT1), at doses that did not affect per se the electrically-induced vasodepressor responses. Interestingly, glibenclamide (an ATP-dependent K(+) channel blocker) attenuated these vasodepressor responses. The present results suggest that AS-19-induced inhibition of the rat vasodepressor sensory CGRPergic outflow is mainly mediated by 5-HT7 receptors via endothelin release, with the possible involvement of ATP-dependent K(+) channels.

Anemia and compliance to oral iron supplementation in a sample of children attending the public health network of Rosario, Santa Fe.

INTRODUCTION: Medicinal iron supplementation is a free and widely used intervention to prevent and treat childhood anemia. OBJECTIVES: To determine the prevalence of anemia in a sample of children from Rosario, to describe the use of iron supplements in children included in the studied sample, and to illustrate variables potentially related to mothers' adherence to oral iron administration. POPULATION AND METHODS: A cross-sectional study involving mothers and infants younger than 42 months old assisted by the public health network of Rosario from December 2011 to April 2012 was conducted. Sociodemographic variables and data on children's health, growth, anemia, and iron administration were collected. A rapid test was used to determine hemoglobin level. RESULTS: A total of 325 mother-infant dyads were included. The overall prevalence of anemia was 40% (95% CI: 35-45%), and it increased up to 56% in the 6-23 month old group. Fifty-one percent of mothers reported that their children had at some time received iron. Mothers' adherence to oral iron administration was higher in the group of children without anemia in comparison to those with anemia (OR: 0.28; 95% CI: 0.1-0.69). The most common causes for lack of adherence included gastrointestinal intolerance (38%) and forgetfulness (36%). CONCLUSIONS: Prevalence of childhood anemia in the studied sample was high. A lower mothers' adherence to iron administration was observed in the group of children with anemia.