Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations?

OBJECTIVE: To investigate whether first trimester exposure to lamotrigine (LTG) monotherapy is specifically associated with an increased risk of orofacial clefts (OCs) relative to other malformations, in response to a signal regarding increased OC risk. METHODS: Population-based case-control study with malformed controls based on EUROCAT congenital anomaly registers. The study population covered 3.9 million births from 19 registries 1995-2005. Registrations included congenital anomaly among livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. Cases were 5,511 nonsyndromic OC registrations, of whom 4,571 were isolated, 1,969 were cleft palate (CP), and 1,532 were isolated CP. Controls were 80,052 nonchromosomal, non-OC registrations. We compared first trimester LTG and antiepileptic drug (AED) use vs nonepileptic non-AED use, for mono and polytherapy, adjusting for maternal age. An additional exploratory analysis compared the observed and expected distribution of malformation types associated with LTG use. RESULTS: There were 72 LTG exposed (40 mono- and 32 polytherapy) registrations. The ORs for LTG monotherapy vs no AED use were 0.67 (95% CI 0.10-2.34) for OC relative to other malformations, 0.80 (95% CI 0.11-2.85) for isolated OC, 0.79 (95% CI 0.03-4.35) for CP, and 1.01 (95% CI 0.03-5.57) for isolated CP. ORs for any AED use vs no AED use were 1.43 (95% CI 1.03-1.93) for OC, 1.21 (95% CI 0.82-1.72) for isolated OC, 2.37 (95% CI 1.54-3.43) for CP, and 1.86 (95% CI 1.07-2.94) for isolated CP. The distribution of other nonchromosomal malformation types with LTG exposure was similar to non-AED exposed. CONCLUSION: We find no evidence of a specific increased risk of isolated orofacial clefts relative to other malformations due to lamotrigine (LTG) monotherapy. Our study is not designed to assess whether there is a generalized increased risk of malformations with LTG exposure.

Role of oxidative stress in plasticity of Dendritic cells

Dendritic cells (DCs) are antigen presenting cells with an unique ability to induce primary immune responses. Different DCs subsets with an intrinsic capacity to polarise Tcells have been described: myeloid (Th1) and lymphoid (Th2). Plasticity is defined as DCs capacity to polarise T cells independent of the DCs origin. We investigated the potential role played by oxidants such as superoxide anion (·O2-), in the plasticity of DCs, measured by the induction of a specific DCs subset, cytokine release and antigen presentation. Furthermore, we are interested in the amplification of immune response analysed by the exosomes production after oxidative stress and LPS stimulation. Recently, we have demonstrated that exposure of cells to superoxide anions resulted in the activation of DC2 profile. To analyse the role of oxidative stress in DCs subsets, we used BDCA-1 and BDCA-2 antibodies, which identify myeloid and plasmacytoid DCs respectively. Freshly isolated monocytes have shown to be BDCA-1-, but BDCA-2+ populations. During 6 days culture up-regulation of BDCA-1, but a down-regulation of BDCA-2 were observed, giving a clear myeloid population. When DC were stimulated with superoxide anions or LPS, we have observed that both down regulate the expression of BDCA-1 when compared to immature DC. Antigen presentation was markedly altered according to the periodicity used, and antigens and oxidants exposures. Using DCs trapped in collagen "matrix" after LPS activation we were able to quantify DCs-exosomes (small membrane vesicles ~50-100 nm in diameter) by reconstruction pictures in three dimensions. Using double vital staining we have found that exosomes from activated DCs can fuse with the membrane of resting DCs. Understanding the capacity of DCs to integrate external signals we will be able to unravel and control Tcells-polarisation triggering a specific immune response or tolerance. We will be able also to understand the amplification role of DCs-exosomes in remote not yet activated DCs.

Fraser syndrome: epidemiological study in a European population.

Fraser syndrome is a rare autosomal recessive disorder characterized by cryptophthalmos, cutaneous syndactyly, laryngeal, and urogenital malformations. We present a population-based epidemiological study using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network of birth defect registries. Between January 1990 and December 2008, we identified 26 cases of Fraser syndrome in the monitored population of 12,886,464 births (minimal estimated prevalence of 0.20 per 100,000 or 1:495,633 births). Most cases (18/26; 69%) were registered in the western part of Europe, where the mean prevalence is 1 in 230,695 births, compared to the prevalence 1 in 1,091,175 for the rest of Europe (P = 0.0003). Consanguinity was present in 7/26 (27%) families. Ten (38%) cases were liveborn, 14 (54%) pregnancies were terminated following prenatal detection of a serious anomaly, and 2 (8%) were stillborn. Eye anomalies were found in 20/24 (83%), syndactyly in 14/24 (58%), and laryngeal anomalies in 5/24 (21%) patients. Ambiguous genitalia were observed in 3/24 (13%) cases. Bilateral renal agenesis was present in 12/24 (50%) and unilateral in 4/24 (17%) cases. The frequency of anorectal anomalies was particularly high (42%). Most cases of Fraser syndrome (85%) are suspected prenatally, often due to the presence of the association of renal agenesis and cryptophthalmos. In the European population, a high proportion (82%) of pregnancies is terminated, thus reducing the live birth prevalence to a third of the total prevalence rate.

Burden of Disease: Environmental Inequalities

A report on Environmental Inequalities in the UK. Part of the Burden of disease. A clean and healthy environment is a vital component of public health. This is particularly so for children. They are more sensitive to most stressors during development and growth and receive relatively more exposure than adults due to behaviour patterns, lack of awareness, size and biological metabolisms.A study of the contribution of environmental pollutants to the incidence, prevalence, mortality and costs of four categories of paediatric disease in American children estimated total annual costs to be $54.9 billion comprising $43.4 billion for lead poisoning, $2.0 billion for asthma, $0.3 billion for childhood cancer, and $9.2 billion for neurobehavioral disorders; 2.8 % of total U.S. health care costs. As well as childhood conditions, some adult diseases, even those that emerge much later in life, e.g. hypertension, hyperlipidemia, insulin resistance, type 2 diabetes, ischemic heart disease, breast cancer and prostate cancer have some of their origins in utero and childhood. Childhood exposures to environmental health hazards may therefore constitute a source of inequity between generations .

Pâturages et pelouses oligotrophes calcicoles du Haut-Jura vaudois: description et écologie

Oligotrophic, lowland and montane meadows and pastures in the Jura Mountains have been well studied, but little is known about subalpine pastures and meadows, especially in Western Switzerland. This paper describes the different types of calcicolous, oligotrophic pastures and meadows found in the "Parc jurassien vaudois" (canton of Vaud). Eight plant communities are described: Gentiano-Brometum acinetosum at montane and Alchemillo-Seslerietum prunelletosum at subalpine altitudes, Alchemillo- Seslerietum festucetosum on shallower soil, Sedo-Poetum acinetosum on very shallow soil, Ranunculi- Agrostietum traunsteineretosum on clayey soil on southern exposures, Seslerio-Laserpitietum on steep and stony southern exposed slopes, a Festuca pulchell a and Pulsatilla alpina community on northern exposed scree, and Laserpitio-Calama- grostietum on more stable scree. Many of these meadows and pastures are very species-rich and deserve protection. Two floristic comparisons complete this paper. The first looks at the transition zone between montane pastures (Mesobromion) and subalpine pastures (Seslerion), and sets the limit around 1350 m, with some variation due to aspect and soil. The second compares the main subalpine pasture community (Alchemillo- Seslerietum prunelletosum) in the Jura Mountains with its vicariant (Seslerio-Caricetum sempervirentis) in the Alps.

Low prevalence of hepatitis C virus infection in Amerindians from Western Venezuela

Previous studies have not found hepatitis C virus (HCV) infection in Amerindians from Western Venezuela. A survey of 254 Bari and Yukpa natives aged 10-60 years (mean ± SD age = 35 ± 5.4 years) from four communities, two Bari and two Yukpa, in this area were studied to assess the prevalence of antibodies to HCV (anti-HCV) and HCV RNA among these indigenous populations. Serum samples were examined initially for anti-HCV by a four generation enzyme-linked immunosorbent assay (ELISA). Reactive samples were then tested using a third generation recombinant immunoblot assay (RIBA-3). Viral RNA was investigated in all immunoblot-reactive samples by a nested polymerase chain reaction (PCR) method. Six (2.3%) of 254 natives were positive by ELISA, one (2.2%) of these reactive samples were positive by RIBA, and four (1.5%) were indeterminate. Only two (0.8%) were positive by PCR, corresponding to 1 (2.1%) of 47 inhabitants of a Yukpa community and to 1 (2.2%) of 45 subjects of a Bari community. Iatrogenic is thought to play a role in acquisition of the infection. The findings indicate a HCV focus of low endemicity and are compatible with a low degree of exposures of the natives to the virus. Studies are necessary to assess the risk factors for infection in these Amerindians.

Preclinical evaluation of implantable cardioverter-defibrillator developed for magnetic resonance imaging use.

BACKGROUND: Many patients with an implantable cardioverter-defibrillator (ICD) have indications for magnetic resonance imaging (MRI). However, MRI is generally contraindicated in ICD patients because of potential risks from hazardous interactions between the MRI and ICD system. OBJECTIVE: The purpose of this study was to use preclinical computer modeling, animal studies, and bench and scanner testing to demonstrate the safety of an ICD system developed for 1.5-T whole-body MRI. METHODS: MRI hazards were assessed and mitigated using multiple approaches: design decisions to increase safety and reliability, modeling and simulation to quantify clinical MRI exposure levels, animal studies to quantify the physiologic effects of MRI exposure, and bench testing to evaluate safety margin. RESULTS: Modeling estimated the incidence of a chronic change in pacing capture threshold >0.5V and 1.0V to be less than 1 in 160,000 and less than 1 in 1,000,000 cases, respectively. Modeling also estimated the incidence of unintended cardiac stimulation to occur in less than 1 in 1,000,000 cases. Animal studies demonstrated no delay in ventricular fibrillation detection and no reduction in ventricular fibrillation amplitude at clinical MRI exposure levels, even with multiple exposures. Bench and scanner testing demonstrated performance and safety against all other MRI-induced hazards. CONCLUSION: A preclinical strategy that includes comprehensive computer modeling, animal studies, and bench and scanner testing predicts that an ICD system developed for the magnetic resonance environment is safe and poses very low risks when exposed to 1.5-T normal operating mode whole-body MRI.

Effective exposure to solar UV in building workers: influence of local and individual factors.

Excessive exposure to solar UV light is the main cause of skin cancers in humans. UV exposure depends on environmental as well as individual factors related to activity. Although outdoor occupational activities contribute significantly to the individual dose received, data on effective exposure are scarce and limited to a few occupations. A study was undertaken in order to assess effective short-term exposure among building workers and characterize the influence of individual and local factors on exposure. The effective exposure of construction workers in a mountainous area in the southern part of Switzerland was investigated through short-term dosimetry (97 dosimeters). Three altitudes, of about 500, 1500 and 2500 m were considered. Individual measurements over 20 working periods were performed using Spore film dosimeters on five body locations. The postural activity of workers was concomitantly recorded and static UV measurements were also performed. Effective exposure among building workers was high and exceeded occupational recommendations, for all individuals for at least one body location. The mean daily UV dose in plain was 11.9 SED (0.0-31.3 SED), in middle mountain 21.4 SED (6.6-46.8 SED) and in high mountain 28.6 SED (0.0-91.1 SED). Measured doses between workers and anatomical locations exhibited a high variability, stressing the role of local exposure conditions and individual factors. Short-term effective exposure ranged between 0 and 200% of ambient irradiation, indicating the occurrence of intense, subacute exposures. A predictive irradiation model was developed to investigate the role of individual factors. Posture and orientation were found to account for at least 38% of the total variance of relative individual exposure, and were also found to account more than altitude on the total variance of effective daily exposures. Targeted sensitization actions through professional information channels and specific prevention messages are recommended. Altitude outdoor workers should also benefit from preventive medical examination.

Travailler sur les articulations interprofessionnelles en périnatalité: un objectif obstétrical [Interprofessional collaboration in perinatality: an obstetrical goal]

In the field of perinatality, development of prenatal diagnosis and neonatal management have been impressive. But these were also associated with the emergence of the increasingly important emotional dimension for parents and professionals. Obstetricians dealing with the difficult breaking of bad news, the uncertainties of prenatal diagnosis and the complex somatic, psychological and social follow-up have to work in a multidisciplinary approach. The securing role of a coherent teamwork is recognised by parents as well as health care providers This article discusses interprofessional relationship as an obstetrical goal and give some landmarks in order to improve the management and the collaboration with parents.

Isolated congenital atrioventricular block diagnosed in utero: natural history and outcome.

BACKGROUND: Isolated congenital atrioventricular block (CAVB) diagnosed in utero is associated with a high morbidity and mortality. Prognosis is especially poor when heart rate drops below 55 beats per minute (bpm) and when fetal hydrops develops. We describe the natural history and outcome of 24 infants with isolated CAVB diagnosed in utero, review the literature, and assess the risk factors that could predict outcome. METHODS: This was a retrospective multicenter study of 24 patients with isolated CAVB diagnosed in utero. RESULTS: CAVB was detected at a mean gestational age (GA) of 24.7 +/- 5.1 weeks. Ten fetuses initially presented with complete heart block. Low heart rate or incomplete heart block was the first documentation of bradyarrhythmia in the other 14 fetuses. In 11 of them, CAVB developed during pregnancy after a median time of 3 (range 1-16) weeks. Fetal hydrops developed in 10 of 24 (42%) fetuses at a mean GA of 27.6 +/- 5.1 weeks. Hydropic fetuses showed lower heart rates during pregnancy (47 +/- 10 bpm) than non-hydropic fetuses (57 +/- 10 bpm). There were three intrauterine deaths; all were hydropic and female. Nine viable females and 12 males were born at a mean GA of 37.1 +/- 6.1 weeks with an average birth weight of 3097 +/- 852 g. Fifteen CAVB patients required pacemaker (PM) intervention, 10 of them immediately after birth. Dilated cardiomyopathy (DCM) developed in three infants of whom two died of congestive heart failure, shortly after the diagnosis was made; one is still alive. Mortality before or after birth was 21%, and was associated with heart rates below 50 bpm and development of fetal hydrops. Poor outcome, defined as death, PM implantation, or development of DCM, occurred in 83% of cases and was associated with heart rates below 60 bpm during pregnancy. CONCLUSIONS: Isolated CAVB diagnosed in utero is associated with high morbidity and mortality. Patients who develop fetal hydrops show lower heart rates during pregnancy than patients who do not. A fetal heart rate below 50 bpm and development of fetal hydrops is associated with increased mortality. Rates below 60 bpm are associated with PM requirement and/or DCM.

Parental occupational exposure to organic solvents and anencephaly in Mexico

Objective: To assess the relationship between parental occupational exposure to organic solvents, and the risk of anencephaly in Mexico. Methods: A case-control study was conducted based on the registers of the Epidemiological Surveillance System for Neural Tube Defects in Mexico; 151 cases of anencephaly of ≥20 weeks’ gestation were included. A control, born alive and without any apparent congenital malformations at birth, was selected for each case in the same maternity service in which the case was born. Information on occupational exposures, lifestyle habits, reproductive history, use of medicines, supplementation with multivitamins and folic acid, was obtained by a general questionnaire; a food frequency questionnaire was also applied to obtain information of daily intake of folate and other B vitamins. Occupational exposure to organic solvents was based on job title as a proxy for exposure and analysed considering two critical periods around conception. Results: In logistic regression analysis, the odds of having a child with anencephaly was higher if the mother or the father was occupationally exposed to organic solvents during the periconceptional period, or when both parents or at least one of them were occupationally exposed during this period with an adjusted odds ratio of 2.97 (95% CI 1.36 to 6.52). Conclusions: The results support the hypothesis that both maternal and paternal occupational exposure to organic solvents can increase the probability of having a child with anencephaly.

Identifying pesticide use patterns among flower growers to assess occupational exposure to mixtures

Objectives Exposure assessment to a single pesticide does not capture the complexity of the occupational exposure. Recently, pesticide use patterns analysis has emerged as an alternative to study these exposures. The aim of this study is to identify the pesticide use pattern among flower growers in Mexico participating in the study on the endocrine and reproductive effects associated with pesticide exposure. Methods A cross-sectional study was carried out to gather retrospective information on pesticide use applying a questionnaire to the person in charge of the participating flower growing farms. Information about seasonal frequency of pesticide use (rainy and dry) for the years 2004 and 2005 was obtained. Principal components analysis was performed. Results Complete information was obtained for 88 farms and 23 pesticides were included in the analysis. Six principal components were selected, which explained more than 70% of the data variability. The identified pesticide use patterns during both years were: 1. fungicides benomyl, carbendazim, thiophanate and metalaxyl (both seasons), including triadimephon during the rainy season, chlorotalonyl and insecticide permethrin during the dry season; 2. insecticides oxamyl, biphenthrin and fungicide iprodione (both seasons), including insecticide methomyl during the dry season; 3. fungicide mancozeb and herbicide glyphosate (only during the rainy season); 4. insecticides metamidophos and parathion (both seasons); 5. insecticides omethoate and methomyl (only rainy season); and 6. insecticides abamectin and carbofuran (only dry season). Some pesticides do not show a clear pattern of seasonal use during the studied years. Conclusions The principal component analysis is useful to summarise a large set of exposure variables into smaller groups of exposure patterns, identifying the mixtures of pesticides in the occupational environment that may have an interactive effect on a particular health effect.

Air pollution exposure during pregnancy and reduced birth size: a prospective birth cohort study in Valencia, Spain

Background Maternal exposure to air pollution has been related to fetal growth in a number of recent scientific studies. The objective of this study was to assess the association between exposure to air pollution during pregnancy and anthropometric measures at birth in a cohort in Valencia, Spain. Methods Seven hundred and eighty-five pregnant women and their singleton newborns participated in the study. Exposure to ambient nitrogen dioxide (NO2) was estimated by means of land use regression. NO2 spatial estimations were adjusted to correspond to relevant pregnancy periods (whole pregnancy and trimesters) for each woman. Outcome variables were birth weight, length, and head circumference (HC), along with being small for gestational age (SGA). The association between exposure to residential outdoor NO2 and outcomes was assessed controlling for potential confounders and examining the shape of the relationship using generalized additive models (GAM). Results For continuous anthropometric measures, GAM indicated a change in slope at NO2 concentrations of around 40 μg/m3. NO2 exposure >40 μg/m3 during the first trimester was associated with a change in birth length of -0.27 cm (95% CI: -0.51 to -0.03) and with a change in birth weight of -40.3 grams (-96.3 to 15.6); the same exposure throughout the whole pregnancy was associated with a change in birth HC of -0.17 cm (-0.34 to -0.003). The shape of the relation was seen to be roughly linear for the risk of being SGA. A 10 μg/m3 increase in NO2 during the second trimester was associated with being SGA-weight, odds ratio (OR): 1.37 (1.01-1.85). For SGA-length the estimate for the same comparison was OR: 1.42 (0.89-2.25). Conclusions Prenatal exposure to traffic-related air pollution may reduce fetal growth. Findings from this study provide further evidence of the need for developing strategies to reduce air pollution in order to prevent risks to fetal health and development.

Options for clinical trials of pre and post-natal treatments for congenital toxoplasmosis

Clinical trials comparing different drug regimens and strategies for the treatment of congenital toxoplasmosis and its clinical manifestations in the liveborn child in different clinical settings should aim at formally evaluating the net benefit of existing treatments and at developing new therapeutic options. Currently, there is no ideal drug for congenital toxoplasmosis; future research should focus on the screening of new active drugs and on their pre-clinical and early clinical development, with a focus on pharmacokinetic/dynamic studies and teratogenicity. For the prenatal treatment of congenital toxoplasmosis, a trial comparing spiramycine to pyrimethamine-sulphadiazine and placebo would allow a formal estimation of the effect of both drugs in infected pregnant women. In newborn children, the net benefit of pyrimethamine-sulphadiazine should also be formally assessed. These trials will be implemented in settings where prenatal screening for Toxoplasma gondii is currently implemented. Trials should be carefully designed to allow for translation to other settings and modelling tools like cost-effectiveness analysis should be used to provide clinicians and founders with the best available evidence to establish recommendations.

Treatment for congenital toxoplasmosis: finding out what works

Evidence for the effectiveness of prenatal or postnatal treatment for congenital toxoplasmosis will be critical to guide policy about prenatal and neonatal screening over the next 10 years, let alone the next 100. Randomised controlled trials are needed to address questions about treatment effectiveness, although cohort studies are also needed to provide information on prognosis, especially disability. Nowhere are such studies needed more than in South America where congenital toxoplasmosis is a major public health problem.