Quantifying circulating hypoxia-induced RNA transcripts in maternal blood to determine in uterofetal hypoxic status

Background

Hypoxia in utero can lead to stillbirth and severe perinatal injury. While current prenatal tests can identify fetuses that are hypoxic, none can determine the severity of hypoxia/acidemia. We hypothesized a hypoxic/acidemic fetus would up-regulate and release hypoxia-induced mRNA from the fetoplacental unit into the maternal circulation, where they can be sampled and quantified. Furthermore, we hypothesized the abundance of hypoxia induced mRNA in the maternal circulation would correlate with severity of fetal hypoxia/acidemia in utero. We therefore examined whether abundance of hypoxia-induced mRNA in the maternal circulation correlates with the degree of fetal hypoxia in utero.

Methods

We performed a prospective study of two cohorts: 1) longitudinal study of pregnant women undergoing an induction of labor (labor induces acute fetal hypoxia) and 2) pregnancies complicated by severe preterm growth restriction (chronic fetal hypoxia). For each cohort, we correlated hypoxia induced mRNA in the maternal blood with degree of fetal hypoxia during its final moments in utero, evidenced by umbilical artery pH or lactate levels obtained at birth. Gestational tissues and maternal bloods were sampled and mRNAs quantified by microarray and RT-PCR.

Results

Hypoxia-induced mRNAs in maternal blood rose across labor, an event that induces acute fetal hypoxia. They exhibited a precipitous increase across the second stage of labor, a particularly hypoxic event. Importantly, a hypoxia gene score (sum of the relative expression of four hypoxia-induced genes) strongly correlated with fetal acidemia at birth. Hypoxia-induced mRNAs were also increased in the blood of women carrying severely growth restricted preterm fetuses, a condition of chronic fetal hypoxia. The hypoxia gene score correlated with the severity of ultrasound Doppler velocimetry abnormalities in fetal vessels. Importantly, the hypoxia gene score (derived from mRNA abundance in maternal blood) was significantly correlated with the degree of fetal acidemia at birth in this growth restriction cohort.

Conclusions

Abundance of mRNAs coding hypoxia-induced genes circulating in maternal blood strongly correlates with degree of fetal hypoxia/acidemia. Measuring hypoxia-induced mRNA in maternal blood may form the basis of a novel non-invasive test to clinically determine the degree of fetal hypoxia/acidemia while in utero.

     

Informatics resources for tuberculosis--towards drug discovery

Integration of biological data on gene sequence, genome annotation, gene expression, metabolic pathways, protein structure, drug target prioritization and selection, has resulted in several online bioinformatics databases and tools for Mycobacterium tuberculosis. Alongside there has been a growth in the list of cheminformatics databases for small molecules and tools to facilitate drug discovery. In spite of these efforts there is a noticeable lag in the drug discovery process which is an urgent need in the case of emerging and re-emerging infectious diseases. For example, more than 25 online databases are available freely for tuberculosis and yet these resources have not been exploited optimally. Informatics-centered drug discovery based on the integration and analysis of both bioinformatics and cheminformatics data could fill in the gap and help to accelerate the process of drug discovery. This article aims to review the current standing of developments in tuberculosis-bioinformatics and highlight areas where integration of existing resources could lead to acceleration of drug discovery against tuberculosis. Such an approach could be adapted for other diseases as well.     

Survey of the use of tests for human papilloma virus and epidermal growth factor receptor for squamous cell carcinoma of the head and neck in UK head and neck multidisciplinary teams

Human papilloma virus (HPV), usually type 16, has emerged as an aetiological and prognostic marker of oropharyngeal carcinomas, and epidermal growth factor receptor (EGFR) has been associated with poor prognosis in patients with carcinoma of the head and neck. This makes the identification of cancers associated with these biomarkers important in the management of patients. We surveyed UK head and neck multidisciplinary teams by email using an online form to assess the use of biomarker testing. Overall 33 cancer networks were contacted and 28 (85%) responded. HPV tests were used in departments by 22 (79%) of our respondents, while only 3 (11%) used EGFR tests. The commonest reasons for not using them were lack of availability and lack of clinical indication.     

Adhesives for the restoration of non-carious cervical lesions: a systematic review

ObjectivesTo establish whether simplified adhesives (self-etch) are as clinically effective as conventional adhesives (etch-and-rinse) with multiple application steps for treatment of non-carious cervical lesions (NCCLs).Null hypothesis: there is no difference in the clinical effectiveness of the four different bonding strategies: Three-step etch-and-rinse; Two-step etch-and-rinse; Two-step self-etch; One-step self-etch for treatment of NCCLs.SourcesElectronic databases were searched including: Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. In addition, studies were identified by handsearching of selected journals.Study selectionRandomised controlled trials (RCTs) comparing at least two adhesives in non-carious cervical lesions (NCCLs), with at least 18 months follow-up were selected. The primary outcome was loss of retention/restoration loss, with marginal adaptation and marginal discolouration as secondary outcomes. Criteria for quality assessment included: random sequence generation; allocation concealment; blinding of outcome assessment; and information on withdrawals. Twenty six studies were identified that met the inclusion criteria. In general, studies were not of sufficient quality to fully address the objectives of this review.ConclusionThere is not enough evidence to support one adhesive or bonding strategy over another for treatment of NCCLs. Consequently, the null hypothesis of no difference cannot be supported or rejected with the data currently available. There is a need for better standardisation and reporting of randomised controlled trials investigating adhesive performance.Clinical significanceStudies with low overall risk of bias demonstrated good clinical performance for adhesives with all four bonding strategies. However, included studies showed wide variation between adhesives of the same category.