Cost and impact of scaling up interventions to save lives of mothers and children: taking South Africa closer to MDGs 4 and 5

KIMBACKGROUND:South Africa has made substantial progress on child and maternal mortality, yet many avoidable deaths of mothers and children still occur. This analysis identifies priority interventions to be scaled up nationally and projects the potential maternal and child lives saved. DESIGN: We modelled the impact of maternal, newborn and child interventions using the Lives Saved Tools Projections to 2015 and used realistic coverage increases based on expert opinion considering recent policy change, financial and resource inputs, and observed coverage change. A scenario analysis was undertaken to test the impact of increasing intervention coverage to 95%. RESULTS:By 2015, with realistic coverage, the maternal mortality ratio (MMR) can reduce to 153 deaths per 100,000 and child mortality to 34 deaths per 1,000 live births. Fifteen interventions, including labour and delivery management, early HIV treatment in pregnancy, prevention of mother-to-child transmission and handwashing with soap, will save an additional 9,000 newborns and children and 1,000 mothers annually. An additional US$370 million (US$7 per capita) will be required annually to scale up these interventions. When intervention coverage is increased to 95%, breastfeeding promotion becomes the top intervention, the MMR reduces to 116 and the child mortality ratio to 23

Elimination of mother- to - child transmission of HIV in South Africa : Rapid scale- up using quality improvement

PKBackground: South Africa (SA) is committed to achieving the goal of eliminating mother-to-child transmission (MTCT) of HIV by 2015. To achieve this, universal coverage of quality antenatal, labour, delivery and postnatal services for all women has to be attained. Over the past decade, the prevention of mother-to-child transmission (PMTCT) programme has been scaled up to reach all healthcare facilities in the country. However, challenges persist in achieving 100% coverage and access to the programme. Objectives: We describe the process undertaken by the National Department of Health (NDoH), in collaboration with partners, to develop, implement and monitor a data-driven intervention to improve facility, district, provincial and national PMTCT-related performance. Methods: Between 2011 and 2013, the NDoH developed and implemented an intervention using data-driven participatory processes to understand facility-level bottlenecks to optimise PMTCT implementation and to scale up priority PMTCT actions nationally. Results: There was remarkable improvement across all key indicators in the PMTCT cascade over the 3 years 2011 - 2013. Simple monitoring tools such as a visual dashboard and data for action reports were successfully used to improve the performance of the PMTCT programme across SA. MTCT has shown a significant downward trend. Conclusions: It is feasible to implement district-level, data-driven quality improvement processes at a national scale to improve the performance of the PMTCT programme at the local level

Cerebrospinal fluid matrix metalloproteinase-9 increases during treatment of recurrent malignant gliomas

<p>Abstract</p> <p>Background</p> <p>Matrix metalloproteinases (MMPs) are enzymes that promote tumor invasion and angiogenesis by enzymatically remodeling the extracellular matrix. MMP-2 and MMP-9 are the most abundant forms of MMPs in malignant gliomas, while a 130 kDa MMP is thought to be MMP-9 complexed to other proteinases. This study determined whether doxycycline can block MMP activity <it>in vitro</it>. We also measured MMP-2 and MMP-9 levels in cerebrospinal fluid (CSF) from patients with recurrent malignant gliomas.</p> <p>Methods</p> <p>To determine whether doxycycline can block MMP activity, we measured the extent of doxycyline-mediated MMP-2 and MMP-9 inhibition <it>in vitro </it>using epidermal growth factor receptor (EGFR) transfected U251 glioma cell lines. MMP activity was measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography. In addition, patients underwent lumbar puncture for CSF sampling at baseline, after 6 weeks (1 cycle), and after 12 weeks (2 cycles), while being treated with a novel chemotherapy regimen of irinotecan, thalidomide, and doxycycline designed to block growth/proliferation, angiogenesis, and invasion. Irinotecan was given at 125 mg/m²/week for 4 weeks in 6-week cycles, together with continuous doxycycline at 100 mg twice daily on Day 1 and 50 mg twice daily thereafter. Daily thalidomide dose in our cohort was 400 mg. Tumor progression was monitored by magnetic resonance imaging (MRI).</p> <p>Results</p> <p>Doxycyline <it>in vitro </it>completely abolished MMP-9 activity at 500 μg/ml while there was only 30 to 50% inhibition of MMP-2 activity. Four patients respectively completed 4, 3, 1, and 2 cycles of irinotecan, thalidomide, and doxycycline. Patient enrollment was terminated after one patient developed radiologically defined pulmonary embolism, and another had probable pulmonary embolism. Although CSF MMP-2 and 130 kDa MMP levels were stable, MMP-9 level progressively increased during treatment despite stable MRI.</p> <p>Conclusion</p> <p>Doxycycline can block MMP-2 and MMP-9 activities from glioma cells <it>in vitro</it>. Increased CSF MMP-9 activity could be a biomarker of disease activity in patients with malignant gliomas, before any changes are detectable on MRI.</p

Retention of Memory through Metamorphosis: Can a Moth Remember What It Learned As a Caterpillar?

Insects that undergo complete metamorphosis experience enormous changes in both morphology and lifestyle. The current study examines whether larval experience can persist through pupation into adulthood in Lepidoptera, and assesses two possible mechanisms that could underlie such behavior: exposure of emerging adults to chemicals from the larval environment, or associative learning transferred to adulthood via maintenance of intact synaptic connections. Fifth instar Manduca sexta caterpillars received an electrical shock associatively paired with a specific odor in order to create a conditioned odor aversion, and were assayed for learning in a Y choice apparatus as larvae and again as adult moths. We show that larvae learned to avoid the training odor, and that this aversion was still present in the adults. The adult aversion did not result from carryover of chemicals from the larval environment, as neither applying odorants to naïve pupae nor washing the pupae of trained caterpillars resulted in a change in behavior. In addition, we report that larvae trained at third instar still showed odor aversion after two molts, as fifth instars, but did not avoid the odor as adults, consistent with the idea that post-metamorphic recall involves regions of the brain that are not produced until later in larval development. The present study, the first to demonstrate conclusively that associative memory survives metamorphosis in Lepidoptera, provokes intriguing new questions about the organization and persistence of the central nervous system during metamorphosis. Our results have both ecological and evolutionary implications, as retention of memory through metamorphosis could influence host choice by polyphagous insects, shape habitat selection, and lead to eventual sympatric speciation

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.

Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies

Search for nonstandard neutrino interactions with IceCube DeepCore

As atmospheric neutrinos propagate through the Earth, vacuumlike oscillations are modified by Standard Model neutral- and charged-current interactions with electrons. Theories beyond the Standard Model introduce heavy, TeV-scale bosons that can produce nonstandard neutrino interactions. These additional interactions may modify the Standard Model matter effect producing a measurable deviation from the prediction for atmospheric neutrino oscillations. The result described in this paper constrains nonstandard interaction parameters, building upon a previous analysis of atmospheric muon-neutrino disappearance with three years of IceCube DeepCore data. The best fit for the muon to tau flavor changing term is εμτ=−0.0005, with a 90% C.L. allowed range of −0.0067<εμτ<0.0081. This result is more restrictive than recent limits from other experiments for εμτ. Furthermore, our result is complementary to a recent constraint on εμτ using another publicly available IceCube high-energy event selection. Together, they constitute the world’s best limits on nonstandard interactions in the μ−τ sector.M.G. Aartsen … G.C. Hill … A. Kyriacou … S. Robertson … A. Wallace … B.J. Whelan … et al. [The IceCube Collaboration

Subjective Distresses of Nasogastric Tube Feeding

Health care professionals assume that tube feeding is an unpleasant, distressing experience for patients, which is only partially substantiated by experience. Thirty patients were interviewed via a tube feeding and hospital experience checklist (a 47–item interview schedule). Common experiences were operationally defined as those felt by at least 50%; subjectively distressful experiences were those identified by patients as causing distress. The most common and most distressful experiences of nasogastric tube feeding were: sensory irritations and sensory deprivation. The psychosensory irritation experiences were: thirst, sore nose or throat, dry mouth, runny nose, a tube in the nose, taking food through a tube, breathing through the mouth, breathing with a tube in the nose, taking food in a treatment type container, and taking food with a different texture and smell than usual. The psychosensory deprivation experiences were: an unsatisfied appetite for certain foods, deprivation of tasting, chewing, swallowing food, and drinking liquids, limited mobility, and deprivation of regular food. Except for burping, gastrointestinal symptoms were not common though they were usually distressful. This information has been used to develop teaching programs which are being tested for effectiveness in reducing distress associated with nasogastric tube feeding.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68702/2/10.1177_014860717900300204.pd

Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons

Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.Howard Hughes Medical InstituteRikagaku Kenkyūjo (Japan

Measurement of atmospheric neutrino oscillations at 6-56 GeV with IceCube DeepCore

We present a measurement of the atmospheric neutrino oscillation parameters using three years of data from the IceCube Neutrino Observatory. The DeepCore infill array in the center of IceCube enables the detection and reconstruction of neutrinos produced by the interaction of cosmic rays in Earth’s atmosphere at energies as low as ∼5  GeV. That energy threshold permits measurements of muon neutrino disappearance, over a range of baselines up to the diameter of the Earth, probing the same range of L/Eν as long-baseline experiments but with substantially higher-energy neutrinos. This analysis uses neutrinos from the full sky with reconstructed energies from 5.6 to 56 GeV. We measure Δm232=2.31+0.11−0.13×10−3  eV2 and sin2θ23=0.51+0.07−0.09, assuming normal neutrino mass ordering. These results are consistent with, and of similar precision to, those from accelerator- and reactor-based experiments.M. G. Aartsen, M. Ackermann, J. Adams, J. A. Aguilar, M. Ahlers … Gary C. Hill … et al

Measurement of atmospheric tau neutrino appearance with IceCube DeepCore

We present a measurement of atmospheric tau neutrino appearance from oscillations with three years of data from the DeepCore subarray of the IceCube Neutrino Observatory. This analysis uses atmospheric neutrinos from the full sky with reconstructed energies between 5.6 and 56 GeV to search for a statistical excess of cascadelike neutrino events which are the signature of ντ interactions. For CC+NC (CC-only) interactions, we measure the tau neutrino normalization to be 0.73⁺·³⁰-.₂₄ (0.57⁺·³⁶-.₃₀) and exclude the absence of tau neutrino oscillations at a significance of 3.2σ (2.0σ) These results are consistent with, and of similar precision to, a confirmatory IceCube analysis also presented, as well as measurements performed by other experiments.M.G. Aartsen … G.C. Hill … A. Kyriacou … A. Wallace … B.J. Whelan … et al. (The IceCube Collaboration