Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke

BACKGROUND: Nitroglycerin (also known as glyceryl trinitrate (GTN)), a vasodilator best known for treatment of ischemic heart disease, has also been investigated for its potential therapeutic benefit in ischemic stroke. The completed Efficacy of Nitric Oxide in Stroke trial suggested that GTN has therapeutic benefit with acute (within 6 hours) transdermal systemic sustained release therapy. OBJECTIVE: To examine an alternative use of GTN as an acute therapy for ischemic stroke following successful recanalization. METHODS: We administered GTN IA following transient middle cerebral artery occlusion in mice. Because no standard dose of GTN is available following emergent large vessel occlusion, we performed a dose-response (3.12, 6.25, 12.5, and 25 µg/µL) analysis. Next, we looked at blood perfusion (flow) through the middle cerebral artery using laser Doppler flowmetry. Functional outcomes, including forced motor movement rotor rod, were assessed in the 3.12, 6.25, and 12.5 µg/µL groups. Histological analysis was performed using cresyl violet for infarct volume, and glial fibrillary activating protein (GFAP) and NeuN immunohistochemistry for astrocyte activation and mature neuron survival, respectively. RESULTS: Overall, we found that acute post-stroke IA GTN had little effect on vessel dilatation after 15 min. Functional analysis showed a significant difference between GTN (3.12 and 6.25 µg/µL) and control at post-stroke day 1. Histological measures showed a significant reduction in infarct volume and GFAP immunoreactivity and a significant increase in NeuN. CONCLUSIONS: These results demonstrate that acute IA GTN is neuroprotective in experimental ischemic stroke and warrants further study as a potentially new stroke therapy

Facial lesions in piglets with intact or grinded teeth

<p>Abstract</p> <p>Background</p> <p>Piglets are born with eight sharp teeth that during nursing can cause facial lesions on littermates and teat lesions on the sow. Teeth grinding in piglets is therefore often practiced to reduce these lesions. The aim of this study was to assess the consequences of grinding piglet teeth in regard to the occurrence of lesions.</p> <p>In this study the piglets' teeth were grinded in 28 litters, and in 36 litters the piglets' teeth were kept intact. Twice, one time during the first week and one time during the second week after birth facial lesions of the piglets were scored and the teats of the sows were examined for lesions. The facial lesion score accounted for the amount and severity of lesions. The individual observations on piglets in the litter were synthesized in a litter facial lesion score.</p> <p>Findings</p> <p>69.8% and 43.5% of the piglets had facial lesions in week 1 and week 2 respectively. The effect of treatment was not significant on litter facial lesion score. The litter facial lesion score was higher in week 1 than in week 2 (<it>p </it>< 0.001) and higher in large litters (<it>p </it>= 0.003) than in small litters. Mortality between week 1 and week 2 was higher in litters with intact teeth (<it>p </it>= 0.02). Sow teat lesions only occurred if litters had intact teeth.</p> <p>Conclusions</p> <p>According to our results teeth grinding is only justifiable in large litters.</p

Tectonic controls on the spatial distribution and stratigraphic architecture of a net-transgressive shallow-marine syn-rift succession in a salt-influenced rift basin: Middle-to-Upper Jurassic, Norwegian Central North Sea

Syn-depositional deformation in salt-influenced rift basins is complex, being driven by a combination of normal faulting and the growth of salt structures such as diapirs. Due to a lack of data with which to simultaneously constrain basin structure and syn-rift stratigraphic architecture, we have a poor understanding of how these processes control shallow marine deposition in such settings. To improve our understanding we here use seismic reflection and borehole data from the Norwegian Central North Sea to investigate the role that syn-depositional fault growth and salt movement played in controlling the sub-regional stratigraphic architecture of a net-transgressive shallow-marine syn-rift succession (Middle-to-Late Jurassic). The rift-related structural framework, which is usually dominated by normal fault-bound horst and graben, is strongly modified where an Upper Permian salt layer (Zechstein Supergroup) is sufficiently thick and mobile to act as an intra-stratal detachment, giving rise to decoupled rift-related basement and cover structural styles. Furthermore, cover extension allows the salt to rise diapirically, resulting in the formation of large salt diapirs and supra-salt normal faults formed due to late-stage salt withdrawal and diapir collapse. Rift-related normal faulting and the growth of salt structures had a dual control on the depositional thickness and facies distribution within the net-transgressive, predominantly shallow-marine, Middle-to-Upper Jurassic syn-rift succession. The resulting facies architecture reflects a delicate balance between fault- and salt flow-driven accommodation creation and intra- and extra-basinal sediment supply. Where sediment supply and accumulation rate exceeded accommodation, little or no change in facies is observed across syn-depositional structures. In contrast, where accommodation outpaced sediment supply and accumulation rate, footwall-attached shorelines locally developed adjacent to large, thick-skinned normal faults, with deeper water conditions persisting in the adjacent hanging wall. Flooding of individual structural elements was strongly diachronous and influenced by the underlying rift-related topography, which was characterised by intra-basinal horst and graben. This paper highlights the key role that salt plays in modifying the tectono-stratigraphic evolution of rift basins, suggesting that existing models, based on salt-free structural templates, need to be modified

Phosphorylation of the androgen receptor is associated with reduced survival in hormonerefractory prostate cancer patients

Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (&lt;i&gt;P&lt;/i&gt;=0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (&lt;i&gt;P&lt;/i&gt;=0.014), and an increase in expression of pAkt&lt;sup&gt;473&lt;/sup&gt; and pAR&lt;sup&gt;210&lt;/sup&gt; were associated with decreased disease-specific survival (&lt;i&gt;P&lt;/i&gt;=0.0019 and 0.0015, respectively). Protein expression of pAkt&lt;sup&gt;473&lt;/sup&gt; and pAR&lt;sup&gt;210&lt;/sup&gt; also strongly correlated (&lt;i&gt;P&lt;/i&gt;&#60;0.001, c.c.=0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target

Fast fluorescence microscopy for imaging the dynamics of embryonic development

Live imaging has gained a pivotal role in developmental biology since it increasingly allows real-time observation of cell behavior in intact organisms. Microscopes that can capture the dynamics of ever-faster biological events, fluorescent markers optimal for in vivo imaging, and, finally, adapted reconstruction and analysis programs to complete data flow all contribute to this success. Focusing on temporal resolution, we discuss how fast imaging can be achieved with minimal prejudice to spatial resolution, photon count, or to reliably and automatically analyze images. In particular, we show how integrated approaches to imaging that combine bright fluorescent probes, fast microscopes, and custom post-processing techniques can address the kinetics of biological systems at multiple scales. Finally, we discuss remaining challenges and opportunities for further advances in this field

Using allocative efficiency analysis to inform health benefits package design for progressing towards Universal Health Coverage: Proof-of-concept studies in countries seeking decision support

Background: Countries are increasingly defining health benefits packages (HBPs) as a way of progressing towards Universal Health Coverage (UHC). Resources for health are commonly constrained, so it is imperative to allocate funds as efficiently as possible. We conducted allocative efficiency analyses using the Health Interventions Prioritization tool (HIPtool) to estimate the cost and impact of potential HBPs in three countries. These analyses explore the usefulness of allocative efficiency analysis and HIPtool in particular, in contributing to priority setting discussions. / Methods and findings: HIPtool is an open-access and open-source allocative efficiency modelling tool. It is preloaded with publicly available data, including data on the 218 cost-effective interventions comprising the Essential UHC package identified in the 3rd Edition of Disease Control Priorities, and global burden of disease data from the Institute for Health Metrics and Evaluation. For these analyses, the data were adapted to the health systems of Armenia, Côte d’Ivoire and Zimbabwe. Local data replaced global data where possible. Optimized resource allocations were then estimated using the optimization algorithm. In Armenia, optimized spending on UHC interventions could avert 26% more disability-adjusted life years (DALYs), but even highly cost-effective interventions are not funded without an increase in the current health budget. In Côte d’Ivoire, surgical interventions, maternal and child health and health promotion interventions are scaled up under optimized spending with an estimated 22% increase in DALYs averted–mostly at the primary care level. In Zimbabwe, the estimated gain was even higher at 49% of additional DALYs averted through optimized spending. / Conclusions: HIPtool applications can assist discussions around spending prioritization, HBP design and primary health care transformation. The analyses provided actionable policy recommendations regarding spending allocations across specific delivery platforms, disease programs and interventions. Resource constraints exacerbated by the COVID-19 pandemic increase the need for formal planning of resource allocation to maximize health benefits

Production of mobile invertebrate communities on shallow reefs from temperate to tropical seas

Primary productivity of marine ecosystems is largely driven by broad gradients in environmental and ecological properties. By contrast, secondary productivity tends to be more variable, influenced by bottom-up (resource-driven) and top-down (predatory) processes, other environmental drivers, and mediation by the physical structure of habitats. Here, we use a continental-scale dataset on small mobile invertebrates (epifauna), common on surfaces in all marine ecosystems, to test influences of potential drivers of temperature-standardized secondary production across a large biogeographic range. We found epifaunal production to be remarkably consistent along a temperate to tropical Australian latitudinal gradient of 28.6°, spanning kelp forests to coral reefs (approx. 3500 km). Using a model selection procedure, epifaunal production was primarily related to biogenic habitat group, which explained up to 45% of total variability. Production was otherwise invariant to predictors capturing primary productivity, the local biomass of fishes (proxy for predation pressure), and environmental, geographical, and human impacts. Highly predictable levels of epifaunal productivity associated with distinct habitat groups across continental scales should allow accurate modelling of the contributions of these ubiquitous invertebrates to coastal food webs, thus improving understanding of likely changes to food web structure with ocean warming and other anthropogenic impacts on marine ecosystems

HCV IRES manipulates the ribosome to promote the switch from translation initiation to elongation.

The internal ribosome entry site (IRES) of the hepatitis C virus (HCV) drives noncanonical initiation of protein synthesis necessary for viral replication. Functional studies of the HCV IRES have focused on 80S ribosome formation but have not explored its role after the 80S ribosome is poised at the start codon. Here, we report that mutations of an IRES domain that docks in the 40S subunit's decoding groove cause only a local perturbation in IRES structure and result in conformational changes in the IRES-rabbit 40S subunit complex. Functionally, the mutations decrease IRES activity by inhibiting the first ribosomal translocation event, and modeling results suggest that this effect occurs through an interaction with a single ribosomal protein. The ability of the HCV IRES to manipulate the ribosome provides insight into how the ribosome's structure and function can be altered by bound RNAs, including those derived from cellular invaders

Motor coordination deficits in Alpk1 mutant mice with the inserted piggyBac transposon

<p>Abstract</p> <p>Background</p> <p>ALPK1 (α-kinase 1) is a member of an unconventional alpha-kinase family, and its biological function remains largely unknown. Here we report the phenotypic characterization of one mutant line, in which the <it>piggyBac </it>(<it>PB</it>) transposon is inserted into the <it>Alpk1 </it>gene.</p> <p>Results</p> <p>The <it>piggyBac</it>(<it>PB</it>) insertion site in mutants was mapped to the first intron of the <it>Alpk1 </it>gene, resulting in the effective disruption of the intact <it>Alpk1 </it>transcript expression. The transposon-inserted <it>Alpk1 </it>homozygous mutants (<it>Alpk1^PB/PB</it>) displayed severe defects in motor coordination in a series of behavioral analysis, including dowel test, hanging wire test, rotarod analysis and footprint analysis. However, the cerebellar architecture, Purkinje cell morphology and electrophysiology of the Purkinje cells appeared normal in mutants. The motor coordination deficits in the <it>Alpk1^PB/PB</it>mice were rescued by transgenic mice expressing the full-length <it>Alpk1</it>-coding sequence under the control of the ubiquitous expression promoter.</p> <p>Conclusions</p> <p>Our results indicate that ALPK1 plays an important role in the regulation of motor coordination. <it>Alpk1^PB/PB</it>mice would be a useful model to provide a clue to the better understanding of the cellular and molecular mechanisms of ALPK1 in the control of fine motor activities.</p