No Association between Antenatal Common Mental Disorders in Low-Obstetric Risk Women and Adverse Birth Outcomes in Their Offspring: Results from the CDS Study in Ghana and C?te D'Ivoire

Background

Evidence linking common mental disorders (CMD) in pregnant women to adverse birth outcomes is inconsistent, and studies often failed to control for pregnancy complications. This study aimed to explore the association between antenatal depression and anxiety symptoms and birth outcomes in a low-obstetric risk sample of mother/child dyads in Ghana and Côte d’Ivoire.

Methods

In 2010-2011, a prospective cohort of 1030 women in their third trimester in Ghana and Côte d’Ivoire was enrolled. Depression and anxiety were assessed in the third trimester using the Patient Health Questionnaire depression module and the 7-item Generalized Anxiety Disorder scale. 719 mother/child dyads were included in the analysis. We constructed multivariate regression models to estimate the association between CMD and low birth weight (LBW), and preterm birth (PTB) to control for potential confounders.

Results

The prevalence of depression and anxiety symptoms were 28.9% and 14.2% respectively. The mean birth weight was 3172.1g (SD 440.6) and the prevalence of LBW was 1.7%. The mean gestational age was 39.6 weeks and the proportion of PTB was 4%. Multivariate linear regression revealed no significant association between maternal depression (B=52.2, 95% CI -18.2 122.6, p=0.15) or anxiety (B=17.1, 95% CI -74.6 108.7, p=0.72) and birth weight. Yet, low socio-economic status, female sex of the child, and younger maternal age were associated with lower birth weight. Multivariate logistic regression suggested no significant association between maternal depression (OR: 2.1, 95% CI 0.8 5.6, p=0.15) or anxiety (OR: 1.8, 95% CI 0.6 5.5, p=0.29) with PTB.

Conclusions

Our data suggests that depression and/or anxiety in the 3^rd trimester of pregnancy are not independent predictors of adverse birth outcomes in low obstetric risk women. The role of pregnancy complications as confounders or effect modifiers in studies of maternal CMD and their impact on birth outcomes should be investigated.     

Transcriptome profile reveals AMPA receptor dysfunction in the hippocampus of the <Emphasis Type="Italic">Rsk2</Emphasis>-knockout mice,an animal model of Coffin–Lowry syndrome

Coffin–Lowry syndrome (CLS) is a syndromic form of mental retardation caused by loss of function mutations in the X-linked RPS6KA3 gene, which encodes RSK2, a serine/threonine kinase acting in the MAPK/ERK pathway. The mouse invalidated for the Rps6ka3 (Rsk2-KO) gene displays learning and long-term spatial memory deficits. In the current study, we compared hippocampal gene expression profiles from Rsk2-KO and normal littermate mice to identify changes in molecular pathways. Differential expression was observed for 100 genes encoding proteins acting in various biological pathways, including cell growth and proliferation, cell death and higher brain function. The twofold up-regulated gene (Gria2) was of particular interest because it encodes the subunit GLUR2 of the AMPA glutamate receptor. AMPA receptors mediate most fast excitatory synaptic transmission in the central nervous system. We provide evidence that in the hippocampus of Rsk2-KO mice, expression of GLUR2 at the mRNA and at the protein levels is significantly increased, whereas basal AMPA receptor-mediated transmission in the hippocampus of Rsk2-KO mice is significantly decreased. This is the first time that such deregulations have been demonstrated in the mouse model of the Coffin–Lowry syndrome. Our findings suggest that a defect in AMPA neurotransmission and plasticity contribute to mental retardation in CLS patients.     

Filariasis Attenuates Anemia and Proinflammatory Responses Associated with Clinical Malaria: A Matched Prospective Study in Children and Young Adults

Background

Wuchereria bancrofti (Wb) and Mansonella perstans (Mp) are blood-borne filarial parasites that are endemic in many countries of Africa, including Mali. The geographic distribution of Wb and Mp overlaps considerably with that of malaria, and coinfection is common. Although chronic filarial infection has been shown to alter immune responses to malaria parasites, its effect on clinical and immunologic responses in acute malaria is unknown.

Methodology/Principal Findings

To address this question, 31 filaria-positive (FIL+) and 31 filaria-negative (FIL−) children and young adults, matched for age, gender and hemoglobin type, were followed prospectively through a malaria transmission season. Filarial infection was defined by the presence of Wb or Mp microfilariae on calibrated thick smears performed between 10 pm and 2 am and/or by the presence of circulating filarial antigen in serum. Clinical malaria was defined as axillary temperature ≥37.5°C or another symptom or sign compatible with malaria infection plus the presence of asexual malaria parasites on a thick blood smear. Although the incidence of clinical malaria, time to first episode, clinical signs and symptoms, and malaria parasitemia were comparable between the two groups, geometric mean hemoglobin levels were significantly decreased in FIL− subjects at the height of the transmission season compared to FIL+ subjects (11.4 g/dL vs. 12.5 g/dL, p<0.01). Plasma levels of IL-1ra, IP-10 and IL-8 were significantly decreased in FIL+ subjects at the time of presentation with clinical malaria (99, 2145 and 49 pg/ml, respectively as compared to 474, 5522 and 247 pg/ml in FIL− subjects).

Conclusions/Significance

These data suggest that pre-existent filarial infection attenuates immune responses associated with severe malaria and protects against anemia, but has little effect on susceptibility to or severity of acute malaria infection. The apparent protective effect of filarial infection against anemia is intriguing and warrants further study in a larger cohort.     

Involvement of fumarase C and NADH oxidase in metabolic adaptation of Pseudomonas fluorescens cells evoked by aluminum and gallium toxicity

Iron (Fe) is a critical element in all aerobic organisms as it participates in a variety of metabolic networks. In this study, aluminum (Al) and gallium (Ga), two Fe mimetics, severely impeded the ability of the soil microbe Pseudomonas fluorescens to perform oxidative phosphorylation. This was achieved by disrupting the activity and expression of complexes I, II, and IV. These toxic metals also inactivated aconitase (ACN) and fumarase A (FUM A), two tricarboxylic acid cycle enzymes dependent on Fe for their catalytic activity, while FUM C, an Fe-independent enzyme, displayed an increase in activity and expression under these stressed situations. Furthermore, in the Al- and Ga-exposed cells, the activity and expression of an H(2)O-forming NADH oxidase were markedly increased. The incubation of the Al- and Ga-challenged cells in an Fe-containing medium led to the recovery of the affected enzymatic activities. Taken together, these data provide novel insights into how environmental pollutants such as Al and Ga interfere with cellular Fe metabolism and also illustrate the ability of Pseudomonas fluorescens to modulate metabolic networks to combat this situation.     

Comparison between clonal and sexual plantlets of Detarium microcarpum Guill. & Perr., a savanna tree species in Burkina Faso

An understanding of the proportion of true seedlings, seedling sprouts and root suckers in the forest is essential for directing the genetic composition of the future crop. We conducted a study to determine the difference between these plantlets of Detarium microcarpum based on morphological characters and carbohydrate contents in leaves and roots. For individuals ≤50 cm in height, root suckers had the highest values for height, stem length, internode number, root diameter, rachis length and leaflet number. The concentrations of starch and total nonstructural carbohydrates in the roots of seedling sprouts were superior. Plantlets did not differ in the concentration of leaf carbohydrates. For individuals >50 cm in height, root suckers had larger values for stem length, root diameter, leaflet length and width. Roots of seedling sprouts showed higher concentrations of soluble sugars and total soluble sugars. True seedlings were distinguished from seedling sprouts and root suckers using all morphological traits except collar diameter and leaflet number. Root suckers and seedling sprouts showed a closer morphological resemblance; thus resulted in slightly more than 50% discrimination success. In conclusion, discrimination between seedling sprouts and root suckers appeared to be more difficult than between true seedlings and clonal plantlets.     

Resting regulatory CD4 T cells: a site of HIV persistence in patients on long-term effective antiretroviral therapy

Background

In HIV-infected patients on long-term HAART, virus persistence in resting long-lived CD4 T cells is a major barrier to curing the infection. Cell quiescence, by favouring HIV latency, reduces the risk of recognition and cell destruction by cytotoxic lymphocytes. Several cell-activation-based approaches have been proposed to disrupt cell quiescence and then virus latency, but these approaches have not eradicated the virus. CD4⁺CD25⁺ regulatory T cells (Tregs) are a CD4⁺ T-cell subset with particular activation properties. We investigated the role of these cells in virus persistence in patients on long-term HAART.

Methodology/Principal Findings

We found evidence of infection of resting Tregs (HLADR⁻CD69⁻CD25^hiFoxP3⁺CD4⁺ T cells) purified from patients on prolonged HAART. HIV DNA harbouring cells appear more abundant in the Treg subset than in non-Tregs. The half-life of the Treg reservoir was estimated at 20 months. Since Tregs from patients on prolonged HAART showed hyporesponsiveness to cell activation and inhibition of HIV-specific cytotoxic T lymphocyte-related functions upon activation, therapeutics targeting cell quiescence to induce virus expression may not be appropriate for purging the Treg reservoir.

Conclusions

Our results identify Tregs as a particular compartment within the latent reservoir that may require a specific approach for its purging.     

Host genetic factors and vaccine-induced immunity to hepatitis B virus infection

Background

Vaccination against hepatitis B virus infection (HBV) is safe and effective; however, vaccine-induced antibody level wanes over time. Peak vaccine-induced anti-HBs level is directly related to antibody decay, as well as risk of infection and persistent carriage despite vaccination. We investigated the role of host genetic factors in long-term immunity against HBV infection based on peak anti-HBs level and seroconversion to anti-HBc.

Methods

We analyzed 715 SNP across 133 candidate genes in 662 infant vaccinees from The Gambia, assessing peak vaccine-induced anti-HBs level and core antibody (anti-HBc) status, whilst adjusting for covariates. A replication study comprised 43 SNPs in a further 393 individuals.

Results

In our initial screen we found variation in IFNG, MAPK8, and IL10RA to affect peak anti-HBs level (GMTratio of <0.6 or >1.5 and P≤0.001) and lesser associations in other genes. Odds of core-conversion was associated with variation in CD163. A coding change in ITGAL (R719V) with likely functional relevance showed evidence of association with increased peak anti-HBs level in both screens (1st screen: s595_22 GMTratio 1.71, P = 0.013; 2nd screen: s595_22 GMTratio 2.15, P = 0.011).

Conclusion

This is to our knowledge the largest study to date assessing genetic determinants of HBV vaccine-induced immunity. We report on associations with anti-HBs level, which is directly related to durability of antibody level and predictive of vaccine efficacy long-term. A coding change in ITGAL, which plays a central role in immune cell interaction, was shown to exert beneficial effects on induction of peak antibody level in response to HBV vaccination. Variation in this gene does not appear to have been studied in relation to immune responses to viral or vaccine challenges previously. Our findings suggest that genetic variation in loci other than the HLA region affect immunity induced by HBV vaccination.     

Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance

Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms. We found that negative feedbacks within MAPK signalling and via the IGF receptor mediate re-activation of MAPK signalling upon treatment in resistant cell lines. By using cell-line specific models, we predict that combinations of MEK inhibitors with RAF or IGFR inhibitors can overcome resistance, and tested these predictions experimentally. In addition, phospho-proteomic profiling confirmed the cell-specific feedback effects and synergy of MEK and IGFR targeted treatment. Our study shows that a quantitative understanding of signalling and feedback mechanisms facilitated by models can help to develop and optimise therapeutic strategies. Our findings should be considered for the planning of future clinical trials introducing MEKi in the treatment of neuroblastoma.     

AN UNUSUAL ECHOCARDIOGRAPHIC PATTERN OF A LEFT ATRIAL MYXOMA

Unusual echocardiographic findings in a 58-year-old woman with a history of rheumatic fever and an angiographically demonstrated prolapsing left atrial myxoma are presented. With variations of gain and damping controls, it was possible to isolate a more distinct anterior mitral leaflet echo, or a more posterior linear echo, thought to represent the prolapsing tumor. The tumor, instead of presenting as a cloud of echoes behind the anterior mitral valve leaflet, demonstrated an alternate pattern of a single linear dense echo at this location. Echocardiography, though very useful in the diagnosis of left atrial tumors, can be fallible at times.