Increasing the Use of Skilled Health Personnel Where Traditional Birth Attendants Were Providers of Childbirth Care: A Systematic Review

Background

Improved access to skilled health personnel for childbirth is a priority strategy to improve maternal health. This study investigates interventions to achieve this where traditional birth attendants were providers of childbirth care and asks what has been done and what has worked?

Methods and Findings

We systematically reviewed published and unpublished literature, searching 26 databases and contacting experts to find relevant studies. We included references from all time periods and locations. 132 items from 41 countries met our inclusion criteria and are included in an inventory; six were intervention evaluations of high or moderate quality which we further analysed. Four studies report on interventions to deploy midwives closer to communities: two studies in Indonesia reported an increase in use of skilled health personnel; another Indonesian study showed increased uptake of caesarean sections as midwives per population increased; one study in Bangladesh reported decreased risk of maternal death. Two studies report on interventions to address financial barriers: one in Bangladesh reported an increase in use of skilled health personnel where financial barriers for users were addressed and incentives were given to skilled care providers; another in Peru reported that use of emergency obstetric care increased by subsidies for preventive and maternity care, but not by improved quality of care.

Conclusions

The interventions had positive outcomes for relevant maternal health indicators. However, three of the studies evaluate the village midwife programme in Indonesia, which limits the generalizability of conclusions. Most studies report on a main intervention, despite other activities, such as community mobilization or partnerships with traditional birth attendants. Many authors note that multiple factors including distance, transport, family preferences/support also need to be addressed. Case studies of interventions in the inventory illustrate how different countries attempted to address these complexities. Few high quality studies that measure effectiveness of interventions exist.     

In silico assessment of potential druggable pockets on the surface of α1-antitrypsin conformers

The search for druggable pockets on the surface of a protein is often performed on a single conformer, treated as a rigid body. Transient druggable pockets may be missed in this approach. Here, we describe a methodology for systematic in silico analysis of surface clefts across multiple conformers of the metastable protein α(1)-antitrypsin (A1AT). Pathological mutations disturb the conformational landscape of A1AT, triggering polymerisation that leads to emphysema and hepatic cirrhosis. Computational screens for small molecule inhibitors of polymerisation have generally focused on one major druggable site visible in all crystal structures of native A1AT. In an alternative approach, we scan all surface clefts observed in crystal structures of A1AT and in 100 computationally produced conformers, mimicking the native solution ensemble. We assess the persistence, variability and druggability of these pockets. Finally, we employ molecular docking using publicly available libraries of small molecules to explore scaffold preferences for each site. Our approach identifies a number of novel target sites for drug design. In particular one transient site shows favourable characteristics for druggability due to high enclosure and hydrophobicity. Hits against this and other druggable sites achieve docking scores corresponding to a K(d) in the μM-nM range, comparing favourably with a recently identified promising lead. Preliminary ThermoFluor studies support the docking predictions. In conclusion, our strategy shows considerable promise compared with the conventional single pocket/single conformer approach to in silico screening. Our best-scoring ligands warrant further experimental investigation.     

Life-history trait and functional diversity patterns of ground beetles and spiders along a coastal heathland successional gradient

We investigated patterns in species richness and diversity, life-history traits and functional diversity of carabid beetles and spiders along a coastal heathland successional gradient. We sampled in five successional stages on the island of Hiddensee, Germany. Species richness of carabids and spiders and Simpson diversity for spiders did not differ among stages. Functional dispersion (FDis), a measure of functional richness, was lowest in the youngest stage for both carabids and spiders. Older successional stages represent more heterogeneous habitats and offer a broader range of niches, which might enhance functional dispersion. Functional evenness (FEve) differed among successional stages for spiders, indicating an uneven distribution of species abundances in the functional trait space. Functional divergence (FDiv) did not differ among stages for either taxon. Shifts in life-history traits were noted in both arthropod groups, but not always in the same direction: Body size of carabid beetles increased towards older successional stages, but decreased for spiders. The number of flightless carabid species increased towards older habitats. Each successional stage seemingly favors species with distinct life-history traits (species sorting). We conclude that a trait-based approach including the use of functional diversity measurements (FDis) could contribute valuable information for biodiversity conservation.     

Effect of air exposure on lysosomal tissues of Mytilus edulis L. from natural intertidal wild beds and submerged culture ropes

Blue mussels collected from suspended culture ropes and from three natural intertidal wild beds from different areas of the German Bight were tested for their ability to cope with hypoxic conditions. During the experiment mussels were exposed to air from 0 to 72 h. Mussels from all sampling sites displayed high tolerance to aerial exposure with moderate levels of mortality after 12 to 48 h of exposure. Lysosomal membrane stability (LMS), a biomarker of general stress, changed notably between minimum values after 12 h and maximum values after 24 h of aerial exposure in intertidal mussels. In contrast, labilization times of mussels from the hanging culture increased continuously up to 48 h of exposure. Intertidal mussels from the island of Heligoland exhibited significantly decreased membrane stability after 72 h of air exposure, correlating to higher mortality rates. Intertidal mussels, although adapted to daily aerial exposure in their natural environment, showed a similar pattern of mortality and lower LMS values during the experiment than mussels from the suspended culture site. The increase of LMS values of mussels under hypoxic conditions at the beginning of the experiment at all sites was tested for the influence of macro-autophagic processes using immune labelling techniques. With this approach it could be demonstrated that high LMS values significantly correlate with low autophagic activity. However, hypoxic conditions do not enhance autophagic processes during the early periods of aerial exposure. Only at the end of the experiment, high values for autophagy were measured in mussels from an intertidal site accompanied with high mortalities. The results indicate that autophagic processes are not involved in the early adaptive processes that enable the mussel to cope with periods of aerial exposure.     

Metabolism of the antibacterial triclocarban by human epidermal keratinocytes to yield protein adducts

Previous studies of triclocarban suggest that its biotransformation could yield reactive metabolites that form protein adducts. Since the skin is the major route of triclocarban exposure, present work examined this possibility in cultured human keratinocytes. The results provide evidence for considerable biotransformation and protein adduct formation when cytochrome P450 activity is induced in the cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a model Ah receptor ligand. Since detecting low adduct levels in cells and tissues is difficult, we utilized the novel approach of accelerator mass spectrometry for this purpose. Exploiting the sensitivity of the method, we demonstrated that a substantial portion of triclocarban forms adducts with keratinocyte protein under the P450 inducing conditions employed.     

Induction of matrix metalloproteinases and TLR2 and 6 in murine colon after oral exposure to Mycobacterium avium subsp. paratuberculosis

Mycobacterium avium subspecies paratuberculosis (MAP) is suspected to be a causative agent in Crohn's disease. Recent evidence suggests that MAP can induce the expression of Matrix Metalloproteinases (MMPs), which are the main proteases in the pathogenesis of mucosal ulcerations in inflammatory bowel disease (IBD). Within the present study, we analysed whether oral MAP exposure can induce colonic MMP expression in vivo. In MAP exposed mice MAP and spheroplasts were visualized in intramucosal leukocyte aggregates. MAP exposed mice exhibited a higher colonic expression of Mmp-2, -9, -13, -14, Timp-1, Tlr2, Tlr6, Il-1β, and Tnf-α. Cell clusters of MMP-9 positive cells adjacent to intramucosal leukocyte aggregates and CD45(+) leukocytes were identified as the major cellular sources of MMP-9. Enhanced TLR2 expression was visualized on the luminal side of colonic enterocytes. Although MAP exposure did not lead to macroscopic intestinal inflammation, the observed MAP spheroplasts in intramucosal leukocyte aggregates together with increased colonic expression of toll-like receptors, pro-inflammatory cytokines, and MMPs upon MAP exposure represents a part of the host immune response towards MAP.     

Helper-dependent canine adenovirus vector-mediated transgene expression in a neurodegenerative lysosomal storage disorder

Mucopolysaccharidosis type IIIA (MPS-IIIA) is a severe neurodegenerative lysosomal storage disorder caused by a deficiency of N-sulfoglucosamine sulfohydrolase (SGSH) activity with subsequent accumulation of partially-degraded heparan sulfate and other glycolipids. In this study, we have evaluated a gene therapy approach using a helper-dependent canine adenovirus vector that expresses human SGSH as a means of delivering sustained transgene expression to the brain. Initial testing in a mixed neural cell culture model demonstrated that the vector could significantly increase SGSH activity in transduced cells, resulting in near-normalization of heparan sulfate-derived fragments. While administration of vector by direct injection into the brain of adult MPS-IIIA mice enabled transgene expression for at least 8.5 months post-treatment, it was only in discrete areas of brain. Heparan sulfate storage was reduced in some regions following treatment, however there was no improvement in secondary neuropathological changes. These data demonstrate that helper-dependent canine adenovirus vectors are capable of neural transduction and mediate long-term transgene expression, but increased SGSH expression throughout the brain is likely to be required in order to effectively treat all aspects of the MPS-IIIA phenotype.     

Targeting the lateral interactions of transmembrane domain 5 of Epstein–Barr virus latent membrane protein 1

The lateral transmembrane protein–protein interaction has been regarded as “undruggable” despite its importance in many biological processes. The homo-trimerization of transmembrane domain 5 (TMD-5) of latent membrane protein 1 (LMP-1) is critical for the constitutive oncogenic activation of the Epstein–Barr virus (EBV). Herein, we report a small molecule agent, NSC 259242 (compound 1), to be a TMD-5 self-association disruptor. Both the positively charged acetimidamide functional groups and the stilbene backbone of compound 1 are essential for its inhibitory activity. Furthermore, cell-based assays revealed that compound 1 inhibits full-length LMP-1 signaling in EBV infected B cells. These studies demonstrated a new strategy for identifying small molecule disruptors for investigating transmembrane protein–protein interactions.     

Knock-down of Pdcd4 stimulates angiogenesis via up-regulation of angiopoietin-2

The tumor suppressor Pdcd4 is involved in multiple pathways. Considering its biological action conflicting data in the literature exist and, consequently, our own studies point to a cell type specific action of Pdcd4. In the present study, using several Pdcd4 knock down cell lines we succeeded to identify angiopoietin-2 (Ang-2) as a gene up-regulated on the mRNA and protein level. The subsequent enhanced peptide secretion forced wild type Bon-1 cells in a neoplastic direction demonstrated by increased proliferation and colony formation while cell adhesion was decreased. Most likely, the stimulation of Ang-2 is in part mediated by increased activation of AP-1 but different signal transduction pathways may also be involved since we found opposite activation of PI3K/Akt/mTOR and MAPK7ERK pathways (both known to regulate in Ang-2 expression). Ang-2 is a modulator of vascular remodeling. Therefore, we analyzed the effect of supernatants from Pdcd4 knock-down cell lines on endothelial cells. Again, we detected reduced cell adhesion and increased colony formation. Probably, the most impressive effect was described on tube formation in a model for angiogenesis. Tube length and junctions of endothelial cells treated with conditioned medium from Pdcd4 knock-down cells were considerably increased. Both, up-regulation of Ang-2 and down-regulation of Pdcd4 are described for many tumors. However, this is the first study showing a direct impact of Pdcd4 on Ang-2 levels and, thereby, angiogenesis. Our data suggest a completely new mechanism for Pdcd4 to act as a tumor suppressor rendering Pdcd4 an attractive target for new therapeutic strategies in cancer treatment.