Evaluation of a single screen and treat strategy to detect asymptomatic malaria among pregnant women from selected health facilities in Lindi region, Tanzania

Background In areas of high transmission, malaria in pregnancy (MiP) primarily causes asymptomatic infections; these infections nonetheless increase the risk of adverse maternal and fetal outcomes. In 2014, Tanzania initiated a single screening and treatment (SST) strategy for all pregnant women at their first antenatal care (ANC) visit using malaria rapid diagnostic tests (RDT) for surveillance purposes. However, there is paucity of data on the effectiveness of SST in the prevention of MiP. The objective of this study was to estimate the number of asymptomatic infections among pregnant women detected by SST, which would have been missed in the absence of the policy. Methods Data from pregnant women attending their first ANC visits between October 2017 and June 2018, including gestational age, history of fever, and RDT results, were abstracted from ANC registers in eight health centres in two randomly selected districts, Kilwa and Lindi, in Lindi Region. The proportion of symptomatic (with history of fever in the past 48 h) and asymptomatic pregnant women with positive RDTs were calculated and stratified by trimester (first, second and third). The study areas were categorized as low transmission with prevalence < 10% or moderate/high with ≥ 10%. Results Over the study period, 1,845 women attended their first ANC visits; 22.1% were in the first trimester (< 12 weeks gestation age). Overall 15.0% of the women had positive RDTs, and there was a trend towards higher malaria prevalence in the first (15.9%) and second (15.2%) trimesters, compared to the third (7.1%), although the differences were not statistically significant (p = 0.07). In total, 6.9% of women reported fever within the past 48 h and, of these, 96.1% were RDT positive. For every 100 pregnant women in the moderate/high and low transmission areas, SST identified 60 and 26 pregnant women, respectively, with asymptomatic infections that would have otherwise been missed. Among the 15.9% of women detected in the first trimester, 50.7% were asymptomatic. Conclusion In areas of moderate/high transmission, many infected women were asymptomatic, and would have been missed in the absence of SST. The benefits on maternal and fetal birth outcomes of identifying these infections depend heavily on the protection afforded by treatment, which is likely to be greatest for women presenting in the first trimester when intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) is contraindicated, and in areas with high SP resistance, such as most parts of Tanzania. An evaluation of the impact and cost-effectiveness of SST across different transmission strata is warranted

Insights into the Molecular Basis of L-Form Formation and Survival in Escherichia coli

L-forms have been shown to occur among many species of bacteria and are suspected to be involved in persistent infections. Since their discovery in 1935, numerous studies characterizing L-form morphology, growth, and pathogenic potential have been conducted. However, the molecular mechanisms underlying the formation and survival of L-forms remain unknown. Using unstable L-form colonies of Escherichia coli as a model, we performed genome-wide transcriptome analysis and screened a deletion mutant library to study the molecular mechanisms involved in formation and survival of L-forms. Microarray analysis of L-form versus classical colonies revealed many up-regulated genes of unknown function as well as multiple over-expressed stress pathways shared in common with persister cells and biofilms. Mutant screens identified three groups of mutants which displayed varying degrees of defects in L-form colony formation. Group 1 mutants, which showed the strongest defect in L-form colony formation, belonged to pathways involved in cell envelope stress, DNA repair, iron homeostasis, outer membrane biogenesis, and drug efflux/ABC transporters. Four (Group 1) mutants, rcsB, a positive response regulator of colanic acid capsule synthesis, ruvA, a recombinational junction binding protein, fur, a ferric uptake regulator and smpA a small membrane lipoprotein were selected for complementation. Complementation of the mutants using a high-copy overexpression vector failed, while utilization of a low-copy inducible vector successfully restored L-form formation. This work represents the first systematic genetic evaluation of genes and pathways involved in the formation and survival of unstable L-form bacteria. Our findings provide new insights into the molecular mechanisms underlying L-form formation and survival and have implications for understanding the emergence of antibiotic resistance, bacterial persistence and latent infections and designing novel drugs and vaccines

The Dynamics of Ca2+ Ions within the Solvation Shell of Calbindin D9k

The encounter of a Ca2+ ion with a protein and its subsequent binding to specific binding sites is an intricate process that cannot be fully elucidated from experimental observations. We have applied Molecular Dynamics to study this process with atomistic details, using Calbindin D9k (CaB) as a model protein. The simulations show that in most of the time the Ca2+ ion spends within the Debye radius of CaB, it is being detained at the 1st and 2nd solvation shells. While being detained near the protein, the diffusion coefficient of the ion is significantly reduced. However, due to the relatively long period of detainment, the ion can scan an appreciable surface of the protein. The enhanced propagation of the ion on the surface has a functional role: significantly increasing the ability of the ion to scan the protein's surface before being dispersed to the bulk. The contribution of this mechanism to Ca2+ binding becomes significant at low ion concentrations, where the intervals between successive encounters with the protein are getting longer. The efficiency of the surface diffusion is affected by the distribution of charges on the protein's surface. Comparison of the Ca2+ binding dynamics in CaB and its E60D mutant reveals that in the wild type (WT) protein the carboxylate of E60 function as a preferred landing-site for the Ca2+ arriving from the bulk, followed by delivering it to the final binding site. Replacement of the glutamate by aspartate significantly reduced the ability to transfer Ca2+ ions from D60 to the final binding site, explaining the observed decrement in the affinity of the mutated protein to Ca2+

Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) maps to the SPG11 locus in the majority of cases. Mutations in the KIAA1840 gene, encoding spatacsin, have been shown to underlie SPG11-linked HSP-TCC. The aim of this study was to perform candidate gene analysis in HSP-TCC subjects from Asian families and to characterize disruption of spatacsin function during zebrafish development. Homozygosity mapping and direct sequencing were used to assess the ACCPN, SPG11, and SPG21 loci in four inbred kindreds originating from the Indian subcontinent. Four novel homozygous SPG11 mutations (c.442+1G>A, c.2146C>T, c.3602_3603delAT, and c.4846C>T) were identified, predicting a loss of spatacsin function in each case. To investigate the role of spatacsin during development, we additionally ascertained the complete zebrafish spg11 ortholog by reverse transcriptase PCR and 5′ RACE. Analysis of transcript expression through whole-mount in situ hybridization demonstrated ubiquitous distribution, with highest levels detected in the brain. Morpholino antisense oligonucleotide injection was used to knock down spatacsin function in zebrafish embryos. Examination of spg11 morphant embryos revealed a range of developmental defects and CNS abnormalities, and analysis of axon pathway formation demonstrated an overall perturbation of neuronal differentiation. These data confirm loss of spatacsin as the cause of SPG11-linked HSP-TCC in Asian kindreds, expanding the mutation spectrum recognized in this disorder. This study represents the first investigation in zebrafish addressing the function of a causative gene in autosomal recessive HSP and identifies a critical role for spatacsin during early neural development in vivo

Combining evidence and values in priority setting: testing the balance sheet method in a low-income country

<p>Abstract</p> <p>Background</p> <p>Procedures for priority setting need to incorporate both scientific evidence and public values. The aim of this study was to test out a model for priority setting which incorporates both scientific evidence and public values, and to explore use of evidence by a selection of stakeholders and to study reasons for the relative ranking of health care interventions in a setting of extreme resource scarcity.</p> <p>Methods</p> <p>Systematic search for and assessment of relevant evidence for priority setting in a low-income country. Development of a balance sheet according to Eddy's explicit method. Eight group interviews (n-85), using a modified nominal group technique for eliciting individual and group rankings of a given set of health interventions.</p> <p>Results</p> <p>The study procedure made it possible to compare the groups' ranking before and after all the evidence was provided to participants. A rank deviation is significant if the rank order of the same intervention differed by two or more points on the ordinal scale. A comparison between the initial rank and the final rank (before deliberation) showed a rank deviation of 67%. The difference between the initial rank and the final rank after discussion and voting gave a rank deviation of 78%.</p> <p>Conclusion</p> <p>Evidence-based and deliberative decision-making does change priorities significantly in an experimental setting. Our use of the balance sheet method was meant as a demonstration project, but could if properly developed be feasible for health planners, experts and health workers, although more work is needed before it can be used for laypersons.</p

Large Scale Comparative Codon-Pair Context Analysis Unveils General Rules that Fine-Tune Evolution of mRNA Primary Structure

BACKGROUND: Codon usage and codon-pair context are important gene primary structure features that influence mRNA decoding fidelity. In order to identify general rules that shape codon-pair context and minimize mRNA decoding error, we have carried out a large scale comparative codon-pair context analysis of 119 fully sequenced genomes. METHODOLOGIES/PRINCIPAL FINDINGS: We have developed mathematical and software tools for large scale comparative codon-pair context analysis. These methodologies unveiled general and species specific codon-pair context rules that govern evolution of mRNAs in the 3 domains of life. We show that evolution of bacterial and archeal mRNA primary structure is mainly dependent on constraints imposed by the translational machinery, while in eukaryotes DNA methylation and tri-nucleotide repeats impose strong biases on codon-pair context. CONCLUSIONS: The data highlight fundamental differences between prokaryotic and eukaryotic mRNA decoding rules, which are partially independent of codon usage

Dopaminergic modulation of affective and social deficits induced by prenatal glucocorticoid exposure

Prenatal stress or exposure to elevated levels of glucocorticoids (GCs) can impair specific neurobehavioral circuits leading to alterations in emotional processes later in life. In turn, emotional deficits may interfere with the quality and degree of social interaction. Here, by using a comprehensive behavioral approach in combination with the measurement of ultrasonic vocalizations, we show that in utero GC (iuGC)-exposed animals present increased immobility in the forced swimming test, pronounced anhedonic behavior (both anticipatory and consummatory), and an impairment in social interaction at different life stages. Importantly, we also found that social behavioral expression is highly dependent on the affective status of the partner. A profound reduction in mesolimbic dopaminergic transmission was found in iuGC animals, suggesting a key role for dopamine (DA) in the etiology of the observed behavioral deficits. Confirming this idea, we present evidence that a simple pharmacological approach—acute L-3,4-dihydroxyphenylacetic acid (L-DOPA) oral administration, is able to normalize DA levels in iuGC animals, with a concomitant amelioration of several dimensions of the emotional and social behaviors. Interestingly, L-DOPA effects in control individuals were not so straightforward; suggesting that both hypo- and hyperdopaminergia are detrimental in the context of such complex behaviors.This work was supported by a grant of Institute for the Study of Affective Neuroscience (ISAN) and Janssen Neurosciences Prize. SB and AJR have Fundacao para a Ciencia e Tecnologia (FCT) fellowships (SFRH/BD/89936/2012; SFRH/BPD/33611/2009)

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. METHODS: We used standard searches to find publications using ADNI data. RESULTS: (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and surrogate outcome measures using longitudinal structural magnetic resonance imaging may further reduce clinical trial cost and duration; (11) Advances in machine learning techniques such as neural networks have improved diagnostic and prognostic accuracy especially in challenges involving MCI subjects; and (12) Network connectivity measures and genetic variants show promise in multimodal classification and some classifiers using single modalities are rivaling multimodal classifiers. DISCUSSION: Taken together, these studies fundamentally deepen our understanding of AD progression and its underlying genetic basis, which in turn informs and improves clinical trial desig

Deinococcus geothermalis: The Pool of Extreme Radiation Resistance Genes Shrinks

Bacteria of the genus Deinococcus are extremely resistant to ionizing radiation (IR), ultraviolet light (UV) and desiccation. The mesophile Deinococcus radiodurans was the first member of this group whose genome was completely sequenced. Analysis of the genome sequence of D. radiodurans, however, failed to identify unique DNA repair systems. To further delineate the genes underlying the resistance phenotypes, we report the whole-genome sequence of a second Deinococcus species, the thermophile Deinococcus geothermalis, which at its optimal growth temperature is as resistant to IR, UV and desiccation as D. radiodurans, and a comparative analysis of the two Deinococcus genomes. Many D. radiodurans genes previously implicated in resistance, but for which no sensitive phenotype was observed upon disruption, are absent in D. geothermalis. In contrast, most D. radiodurans genes whose mutants displayed a radiation-sensitive phenotype in D. radiodurans are conserved in D. geothermalis. Supporting the existence of a Deinococcus radiation response regulon, a common palindromic DNA motif was identified in a conserved set of genes associated with resistance, and a dedicated transcriptional regulator was predicted. We present the case that these two species evolved essentially the same diverse set of gene families, and that the extreme stress-resistance phenotypes of the Deinococcus lineage emerged progressively by amassing cell-cleaning systems from different sources, but not by acquisition of novel DNA repair systems. Our reconstruction of the genomic evolution of the Deinococcus-Thermus phylum indicates that the corresponding set of enzymes proliferated mainly in the common ancestor of Deinococcus. Results of the comparative analysis weaken the arguments for a role of higher-order chromosome alignment structures in resistance; more clearly define and substantially revise downward the number of uncharacterized genes that might participate in DNA repair and contribute to resistance; and strengthen the case for a role in survival of systems involved in manganese and iron homeostasis

Enriched Environment Experience Overcomes Learning Deficits and Depressive-Like Behavior Induced by Juvenile Stress

Mood disorders affect the lives and functioning of millions each year. Epidemiological studies indicate that childhood trauma is predominantly associated with higher rates of both mood and anxiety disorders. Exposure of rats to stress during juvenility (JS) (27–29 days of age) has comparable effects and was suggested as a model of induced predisposition for these disorders. The importance of the environment in the regulation of brain, behavior and physiology has long been recognized in biological, social and medical sciences. Here, we studied the effects of JS on emotional and cognitive aspects of depressive-like behavior in adulthood, on Hypothalamic-Pituitary-Adrenal (HPA) axis reactivity and on the expression of cell adhesion molecule L1 (L1-CAM). Furthermore, we combined it with the examination of potential reversibility by enriched environment (EE) of JS – induced disturbances of emotional and cognitive aspects of behavior in adulthood. Three groups were tested: Juvenile Stress –subjected to Juvenile stress; Enriched Environment – subjected to Juvenile stress and then, from day 30 on to EE; and Naïves. In adulthood, coping and stress responses were examined using the elevated plus-maze, open field, novel setting exploration and two way shuttle avoidance learning. We found that, JS rats showed anxiety- and depressive-like behaviors in adulthood, altered HPA axis activity and altered L1-CAM expression. Increased expression of L1-CAM was evident among JS rats in the basolateral amygdala (BLA) and Thalamus (TL). Furthermore, we found that EE could reverse most of the effects of Juvenile stress, both at the behavioral, endocrine and at the biochemical levels. The interaction between JS and EE resulted in an increased expression of L1-CAM in dorsal cornu ammonis (CA) area 1 (dCA1)