Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects.

Five years after the identification of Zika virus as a human teratogen, we reviewed the early clinical manifestations, collectively called congenital Zika syndrome (CZS). Children with CZS have a very poor prognosis with extremely low performance in motor, cognitive, and language development domains, and practically all feature severe forms of cerebral palsy. However, these manifestations are the tip of the iceberg, with some children presenting milder forms of deficits. Additionally, neurodevelopment can be in the normal range in the majority of the non-microcephalic children born without brain or eye abnormalities. Vertical transmission and the resulting disruption in development of the brain are much less frequent when maternal infection occurs in the second half of the pregnancy. Experimental studies have alerted to the possibility of other behavioral outcomes both in prenatally infected children and in postnatal and adult infections. Cofactors play a vital role in the development of CZS and involve genetic, environmental, nutritional, and social determinants leading to the asymmetric distribution of cases. Some of these social variables also limit access to multidisciplinary professional treatment.

Investigating the role of EGF-CFC gene family in recurrent pregnancy loss through bioinformatics and molecular approaches.

Recurrent pregnancy loss (RPL) is the most common reproductive failure, reaching 1-5% of women throughout their lives, and having unknown etiology in 50% of the cases. In humans, EGF-CFC1 (Epidermal Growth Factors & Cripto/FRL-1/Cryptic) gene family is composed by TDGF1 and CFC1, two developmental genes. The aim of this study was to investigate the role of EGF-CFC on RPL. To this, multiple approaches were performed; we conducted an expression analysis of TDGF1 and CFC1 using publicly available data from Gene Omnibus Expression (GEO), systems biology analyses and functional prediction; and a molecular analysis carried out in a case-control study. Our GEO analysis showed a decrease in TDGF1 expression in the endometrium (p=0.049) and CFC1 expression in placenta (p=0.015) of women with RPL. Network analysis, gene ontology and literature pointed to a strong connection between EGF-CFC1 gene family to pathways that play key roles during pregnancy, including TGF-ß, c-Src/MAPK/AKT, Notch, TNFα, IFNγ and IL-6. A pathogenicity score developed for this gene family showed that the c.-14+1429T>C (rs3806702) variant in the TDGF1 and the p.Arg47Gln (rs201431919) variant in CFC1 gene would be the ones with the highest deleterious effect for RPL. In the case-control study, which involved 149 women with RPL and 159 controls, no statistical difference was observed in the allele and genotype distributions of the variants studied in the two groups. In this study, we performed extensive bioinformatics analysis for biomarker prioritization followed by experimental validation of proposed selected markers. Although there is no statistical difference in the frequencies of these variants between RPL and controls, the expression analysis results suggest that TDGF1 and CFC1 genes might play a role in RPL. In addition, systems biology analyzes raise the hypothesis that genes in other signaling pathways that may be related to RPL as good candidates for future studies.Abbreviations RPL: recurrent pregnancy loss; EGF-CFC1: Epidermal Growth Factors - Cripto/FRL-1; GEO: Gene Omnibus Expression; KEGG: Kyoto Encyclopedia of Genes and Genomes.

Zika virus infection and congenital anomalies in the Americas: opportunities for regional action.

The Zika virus (ZIKV) was identified in 1947 in the Zika forest in Uganda, but recently it has emerged as a public health threat. The first evidence of human infection occurred in 1952, but only in April 2007 was the first outbreak in humans recognized. In the Americas, a ZIKV outbreak began in Brazil in 2015, and from the second half of 2015 onward, a substantial number of newborns with severe microcephaly began to be reported to health authorities. In February 2016, the World Health Organization (WHO) declared that the clusters of microcephaly cases in areas affected by ZIKV constituted a Public Health Emergency of International Concern. Seldom has there been such a resultingly vast production of scientific literature in record time. In this report we discuss the impact of ZIKV infection during pregnancy, the diagnosis and surveillance of microcephaly, the recognition of a clinical phenotype of ZIKV congenital infection, and opportunities for public health action. We consider this to be a unique opportunity for countries in the Region of the Americas to develop, strengthen, and improve surveillance systems for congenital anomalies and teratogen information services. Creating health needs assessment tools for low- and middle-income countries may help them to develop effective policies to ensure primary, secondary, and tertiary prevention measures for congenital anomalies. Such initiatives will be useful for ZIKV congenital syndrome control and also for having a much wider impact on a significant proportion of preventable and manageable congenital conditions.

El virus del Zika (ZIKV) se identificó en 1947 en el bosque de Zika, en Uganda, pero recientemente ha surgido como una amenaza para la salud pública. Los primeros datos de la infección en seres humanos surgieron en 1952, pero no fue hasta abril del 2007 que se reconoció el primer brote en seres humanos. En la Región de las Américas, en el 2015 se inició un brote del virus en el Brasil, y desde la segunda mitad de ese año en adelante se empezó a notificar a las autoridades de salud un número considerable de recién nacidos con microcefalia grave. En febrero del 2016, la Organización Mundial de la Salud (OMS) declaró que los conglomerados de casos de microcefalia detectadas en las zonas afectadas por el ZIKV constituían una emergencia de salud pública de importancia internacional. Raramente ha habido una consiguiente producción tan vasta de publicaciones científicas en un tiempo récord. En este informe se aborda la repercusión de la infección por el ZIKV durante el embarazo, el diagnóstico y la vigilancia de la microcefalia, el reconocimiento de un fenotipo clínico de la infección congénita por el ZIKV y las oportunidades para las intervenciones de salud pública. Consideramos que se trata de una oportunidad única para los países de la Región de las Américas de desarrollar, fortalecer y mejorar los sistemas de vigilancia de las anomalías congénitas y los servicios de información sobre teratógenos. La creación de herramientas de evaluación de las necesidades de salud para los países de ingresos bajos y medianos puede ayudarles a elaborar políticas eficaces destinadas a asegurar medidas preventivas primarias, secundarias y terciarias para las anomalías congénitas. Dichas iniciativas serán útiles para el control del síndrome congénito del ZIKV y también para tener una incidencia mucho mayor sobre una proporción significativa de las enfermedades congénitas prevenibles y controlables.

O vírus Zika (ZIKV) foi identificado em 1947 em animais na floresta de Zika, em Uganda, mas se tornou um grande risco à saúde pública nos últimos anos. A primeira evidência de infecção humana data de 1952, porém o primeiro surto em seres humanos foi registrado somente em abril de 2007. Na Região das Américas, o Brasil registrou um surto de zika em 2015 e, a partir de meados daquele ano, passou a ser notificado aos órgãos de saúde um número considerável de casos de recém-nascidos com microcefalia grave. Em fevereiro de 2016, a Organização Mundial da Saúde (OMS) decretou que a concentração de casos de microcefalia nas áreas de ocorrência de zika representava uma situação de emergência em saúde pública de interesse internacional. Raras vezes se viu tamanha produção de conhecimento científico em tão pouco tempo. Este artigo examina as consequências da infecção pelo vírus Zika durante a gestação, discorre sobre o diagnóstico e a vigilância de casos de microcefalia e a identificação de um fenótipo clínico da infecção congênita pelo ZIKVS e aponta oportunidades para ação em saúde pública. Os autores consideram ser esta uma oportunidade única aos países da Região das Américas de expandir a capacidade e reforçar e melhorar a qualidade dos sistemas de vigilância de malformações congênitas e os serviços de informação sobre teratogenicidade. Desenvolver instrumentos para avaliar as necessidades em saúde dos países de baixa e média renda pode favorecer a formulação de políticas eficazes que garantam medidas de prevenção primária, secundária e terciária de malformações congênitas. Tais iniciativas possibilitariam o controle da síndrome congênita do zika e também poderiam repercutir mais amplamente em um conjunto importante de afecções congênitas que podem ser prevenidas e controladas.