Translating research into policy and practice in developing countries: a case study of magnesium sulphate for pre-eclampsia.

BACKGROUND: The evidence base for improving reproductive health continues to grow. However, concerns remain that the translation of this evidence into appropriate policies is partial and slow. Little is known about the factors affecting the use of evidence by policy makers and clinicians, particularly in developing countries. The objective of this study was to examine the factors that might affect the translation of randomised controlled trial (RCT) findings into policies and practice in developing countries. METHODS: The recent publication of an important RCT on the use of magnesium sulphate to treat pre-eclampsia provided an opportunity to explore how research findings might be translated into policy. A range of research methods, including a survey, group interview and observations with RCT collaborators and a survey of WHO drug information officers, regulatory officials and obstetricians in 12 countries, were undertaken to identify barriers and facilitators to knowledge translation. RESULTS: It proved difficult to obtain reliable data regarding the availability and use of commonly used drugs in many countries. The perceived barriers to implementing RCT findings regarding the use of magnesium sulphate for pre-eclampsia include drug licensing and availability; inadequate and poorly implemented clinical guidelines; and lack of political support for policy change. However, there were significant regional and national differences in the importance of specific barriers. CONCLUSION: The policy changes needed to ensure widespread availability and use of magnesium sulphate are variable and complex. Difficulties in obtaining information on availability and use are combined with the wide range of barriers across settings, including a lack of support from policy makers. This makes it difficult to envisage any single intervention strategy that might be used to promote the uptake of research findings on magnesium sulphate into policy across the study settings. The publication of important trials may therefore not have the impacts on health care that researchers hope for

Maternal Inflammation at Mid-gestation in Pregnant Rats Impairs Fetal Muscle Growth and Development at Term

Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality. Low birth weight resulting from preterm birth and/or IUGR is an underlying factor in 60–80% of perinatal death worldwide, and is particularly common in developing countries (UNICEF, 2008). Furthermore, studies have linked IUGR and the associated fetal malnutrition to increased incidence of metabolic syndrome in adult life (Barker et al., 1993; Godfrey and Barker, 2000). The “thrifty phenotype hypothesis” developed by David Barker (Hales et al., 1991) states that IUGR-associated fetal malnutrition forces the fetus to spare nutrients by altering tissue-specific metabolism in order to survive. In utero, adaptive changes disproportionately impact skeletal muscle development, growth, and metabolism (Yates et al., 2016). Skeletal muscle is responsible for the majority of insulin-stimulated glucose utilization, and adaptive restriction in muscle growth capacity helps to spare glucose in the IUGR fetus but result in lifelong deficits in muscle mass and metabolic homeostasis (Brown and Hay, 2016). Skeletal muscle growth requires proliferation, differentiation, and fusion of myoblast into new muscle fibers early in gestation and fusion with existing fibers in the third trimester of pregnancy (Zhu et al., 2004). This process can be impaired by inflammation from resident macrophages within skeletal muscle. Classically activated M1 macrophages are pro-inflammatory but can polarize to an anti-inflammatory M2 phenotype that inhibits cytokine production and stimulates tissue repair by producing growth factors (Mantovani et al., 2004; Kharraz et al., 2013). The acute effects of inflammatory factors on myoblast function have been investigated in vitro (Frost et al., 1997; Guttridge et al., 2000), and we postulate that inflammatory stress may have similar effects on fetal myoblasts in utero. Impaired myoblast function and the resulting decrease in muscle growth capacity affect long-term metabolic health. Therefore, the objective of this study was to determine the effect of sustained maternal inflammation at mid-gestation on fetal mortality, muscle growth, and metabolic parameters at term

Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products

Photoluminescence spectroscopy of bandgap reduction in dilute InNAs alloys

Photoluminescence (PL) has been observed from dilute InNxAs1–x epilayers grown by molecular-beam epitaxy. The PL spectra unambiguously show band gap reduction with increasing N content. The variation of the PL spectra with temperature is indicative of carrier detrapping from localized to extended states as the temperature is increased. The redshift of the free exciton PL peak with increasing N content and temperature is reproduced by the band anticrossing model, implemented via a (5×5) k·p Hamiltonian

A novel compartment, the 'subqpical stem' of the aerial hyphae, is the location of a sigN-dependent, developmentally distinct transcription in Streptomyces coelicolor.

Streptomyces coelicolor has nine SigB-like RNA polymerase sigma factors, several of them implicated in morphological differentiation and/or responses to different stresses. One of the nine, SigN, is the focus of this article. A constructed sigN null mutant was delayed in development and exhibited a bald phenotype when grown on minimal medium containing glucose as carbon source. One of two distinct sigN promoters, sigNP1, was active only during growth on solid medium, when its activation coincided with aerial hyphae formation. Transcription from sigNP1 was readily detected in several whi mutants (interrupted in morphogenesis of aerial mycelium into spores), but was absent from all bld mutants tested, suggesting that sigNP1 activity was restricted to the aerial hyphae. It also depended on sigN, thus sigN was autoregulated. Mutational and transcription studies revealed no functional significance to the location of sigN next to sigF, encoding another SigB-like sigma factor. We identified another potential SigN target, nepA, encoding a putative small secreted protein. Transcription of nepA originated from a single, aerial hyphae-specific and sigN-dependent promoter. While in vitro run-off transcription using purified SigN on the Bacillus subtilis ctc promoter confirmed that SigN is an RNA polymerase sigma factor, SigN failed to initiate transcription from sigNP1 and from the nepA promoter in vitro. Additional in vivo data indicated that further nepA upstream sequences, which are likely to bind a potential activator, are required for successful transcription. Using a nepA–egfp transcriptional fusion we located nepA transcription to a novel compartment, the ‘subapical stem’ of the aerial hyphae. We suggest that this newly recognized compartment defines an interface between the aerial and vegetative parts of the Streptomyces colony and might also be involved in communication between these two compartments

Thermochemistry of Alane Complexes for Hydrogen Storage: A Theoretical and Experimental Comparison

Knowledge of the relative stabilities of alane (AlH3) complexes with electron donors is essential for identifying hydrogen storage materials for vehicular applications that can be regenerated by off-board methods; however, almost no thermodynamic data are available to make this assessment. To fill this gap, we employed the G4(MP2) method to determine heats of formation, entropies, and Gibbs free energies of formation for thirty-eight alane complexes with NH3-nRn (R = Me, Et; n = 0-3), pyridine, pyrazine, triethylenediamine (TEDA), quinuclidine, OH2-nRn (R = Me, Et; n = 0-2), dioxane, and tetrahydrofuran (THF). Monomer, bis, and selected dimer complex geometries were considered. Using these data, we computed the thermodynamics of the key formation and dehydrogenation reactions that would occur during hydrogen delivery and alane regeneration, from which trends in complex stability were identified. These predictions were tested by synthesizing six amine-alane complexes involving trimethylamine, triethylamine, dimethylethylamine, TEDA, quinuclidine, and hexamine, and obtaining upper limits of delta G for their formation from metallic aluminum. Combining these computational and experimental results, we establish a criterion for complex stability relevant to hydrogen storage that can be used to assess potential ligands prior to attempting synthesis of the alane complex. Based on this, we conclude that only a subset of the tertiary amine complexes considered and none of the ether complexes can be successfully formed by direct reaction with aluminum and regenerated in an alane-based hydrogen storage system.Comment: Accepted by the Journal of Physical Chemistry

A Randomized Phase II Trial of Pioglitazone for Lung Cancer Chemoprevention in High Risk Current and Former Smokers

Lung cancer chemoprevention, especially in high-risk former smokers, has great potential to reduce lung cancer incidence and mortality. Thiazolidinediones prevent lung cancer in preclinical studies, and diabetics receiving thiazolidinediones have lower lung cancer rates which led to our double-blind, randomized, phase II placebo-controlled trial of oral pioglitazone in high risk current or former smokers with sputum cytologic atypia or known endobronchial dysplasia. Bronchoscopy was performed at study entry and after completing of six months of treatment. Biopsies were histologically scored, and primary endpoint analysis tested worst biopsy scores (Max) between groups; Dysplasia index (DI) and average score (Avg) changes were secondary endpoints. Biopsies also received an inflammation score. The trial accrued 92 subjects (47 pioglitazone, 45 placebo), and 76 completed both bronchoscopies (39 pioglitazone, 37 placebo). Baseline dysplasia was significantly worse for current smokers, and 64% of subjects had mild or greater dysplasia at study entry. Subjects receiving pioglitazone did not exhibit improvement in bronchial dysplasia. Former smokers treated with pioglitazone exhibited a slight improvement in Max, while current smokers exhibited slight worsening. While statistically significant changes in Avg and DI were not observed in the treatment group, former smokers exhibited a slight decrease in both Avg and DI. Negligible Avg and DI changes occurred in current smokers. A trend towards decreased Ki-67 labeling index occurred in former smokers with baseline dysplasia receiving pioglitazone. While pioglitazone did not improve endobronchial histology in this high-risk cohort, specific lesions showed histologic improvement and further study is needed to better characterize responsive dysplasia

Candida albicans repetitive elements display epigenetic diversity and plasticity

Transcriptionally silent heterochromatin is associated with repetitive DNA. It is poorly understood whether and how heterochromatin differs between different organisms and whether its structure can be remodelled in response to environmental signals. Here, we address this question by analysing the chromatin state associated with DNA repeats in the human fungal pathogen Candida albicans. Our analyses indicate that, contrary to model systems, each type of repetitive element is assembled into a distinct chromatin state. Classical Sir2-dependent hypoacetylated and hypomethylated chromatin is associated with the rDNA locus while telomeric regions are assembled into a weak heterochromatin that is only mildly hypoacetylated and hypomethylated. Major Repeat Sequences, a class of tandem repeats, are assembled into an intermediate chromatin state bearing features of both euchromatin and heterochromatin. Marker gene silencing assays and genome-wide RNA sequencing reveals that C. albicans heterochromatin represses expression of repeat-associated coding and non-coding RNAs. We find that telomeric heterochromatin is dynamic and remodelled upon an environmental change. Weak heterochromatin is associated with telomeres at 30?°C, while robust heterochromatin is assembled over these regions at 39?°C, a temperature mimicking moderate fever in the host. Thus in C. albicans, differential chromatin states controls gene expression and epigenetic plasticity is linked to adaptation

Prenatal muscle development in a mouse model for the secondary dystroglycanopathies

The defective glycosylation of α-dystroglycan is associated with a group of muscular dystrophies that are collectively referred to as the secondary dystroglycanopathies. Mutations in the gene encoding fukutin-related protein (FKRP) are one of the most common causes of secondary dystroglycanopathy in the UK and are associated with a wide spectrum of disease. Whilst central nervous system involvement has a prenatal onset, no studies have addressed prenatal muscle development in any of the mouse models for this group of diseases. In view of the pivotal role of α-dystroglycan in early basement membrane formation, we sought to determine if the muscle formation was altered in a mouse model of FKRP-related dystrophy