Innate immune response to intramammary infection with Serratia marcescens and Streptococcus uberis

Streptococcus uberis and Serratia marcescens are Gram-positive and Gram-negative bacteria, respectively, that induce clinical mastitis. Once initial host barrier systems have been breached by these pathogens, the innate immune system provides the next level of defense against these infectious agents. The innate immune response is characterized by the induction of pro-inflammatory cytokines, as well as increases in other accessory proteins that facilitate host recognition and elimination of the pathogens. The objective of the current study was to characterize the innate immune response during clinical mastitis elicited by these two important, yet less well-studied, Gram-positive and Gram-negative organisms. The pro-inflammatory cytokine response and changes in the levels of the innate immune accessory recognition proteins, soluble CD14 (sCD14) and lipopolysaccharide (LPS)-binding protein (LBP), were studied. Decreased milk output, induction of a febrile response, and increased acute phase synthesis of LBP were all characteristic of the systemic response to intramammary infection with either organism. Infection with either bacteria similarly resulted in increased milk levels of IL-1$\beta$, IL-8, IL-10, IL-12, IFN-$\gamma$, TNF-$\alpha$, sCD14, LBP, and the complement component, C5a. However, the duration of and/or maximal changes in the increased levels of these inflammatory markers were significantly different for several of the inflammatory parameters assayed. In particular, S. uberis infection was characterized by the sustained elevation of higher milk levels of IL-1$\beta$, IL-10, IL-12, IFN-$\gamma$, and C5a, relative to S. marcescens infection. Together, these data demonstrate the variability of the innate immune response to two distinct mastitis pathogens

Left-right dissociation of hippocampal memory processes in mice.

Left-right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3-CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left-right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left-right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory.http://dx.doi.org/10.1073/pnas.1405648111This is the author's accepted manuscript. It will be under embargo for 6 months from the date of publication. The final version is available from PNAS at http://www.pnas.org/content/early/2014/09/16/1405648111.abstract

Ethnicity and the Writing of Medieval Scottish history

Historians have long tended to define medieval Scottish society in terms of interactions between ethnic groups. This approach was developed over the course of the long nineteenth century, a formative period for the study of medieval Scotland. At that time, many scholars based their analysis upon scientific principles, long since debunked, which held that medieval 'peoples' could only be understood in terms of 'full ethnic packages'. This approach was combined with a positivist historical narrative that defined Germanic Anglo-Saxons and Normans as the harbingers of advances of Civilisation. While the prejudices of that era have largely faded away, the modern discipline still relies all too often on a dualistic ethnic framework. This is particularly evident in a structure of periodisation that draws a clear line between the 'Celtic' eleventh century and the 'Norman' twelfth. Furthermore, dualistic oppositions based on ethnicity continue, particularly in discussions of the law, kingship, lordship and religion

Histone Deacetylase Inhibitors Prevent Pulmonary Endothelial Hyperpermeability and Acute Lung Injury By Regulating Heat Shock Protein 90 Function

Transendothelial hyperpermeability caused by numerous agonists is dependent on heat shock protein 90 (Hsp90) and leads to endothelial barrier dysfunction (EBD). Inhibition of Hsp90 protects and restores transendothelial permeability. Hyperacetylation of Hsp90, as by inhibitors of histone deacetylase (HDAC), suppresses its chaperone function and mimics the effects of Hsp90 inhibitors. In this study we assessed the role of HDAC in mediating lipopolysaccharide (LPS)-induced transendothelial hyperpermeability and acute lung injury (ALI). We demonstrate that HDAC inhibition protects against LPS-mediated EBD. Inhibition of multiple HDAC by the general inhibitors panobinostat or trichostatin provided protection against LPS-induced transendothelial hyperpermeability, acetylated and suppressed Hsp90 chaperone function, and attenuated RhoA activity and signaling crucial to endothelial barrier function. Treatment with the HDAC3-selective inhibitor RGFP-966 or the HDAC6-selective inhibitor tubastatin A provided partial protection against LPS-mediated transendothelial hyperpermeability. Similarly, knock down of HDAC3 and HDAC6 by specific small-interfering RNAs provided significant protection against LPS-induced EBD. Furthermore, combined pharmacological inhibition of both HDAC3 and -6 attenuated the inflammation, capillary permeability, and structural abnormalities associated with LPS-induced ALI in mice. Together these data indicate that HDAC mediate increased transendothelial hyperpermeability caused by LPS and that inhibition of HDAC protects against LPS-mediated EBD and ALI by suppressing Hsp90-dependent RhoA activity and signaling

Risk of Uterine Rupture and Placenta Accreta With Prior Uterine Surgery Outside of the Lower Segment

Objective—Women with a prior myomectomy or prior classical cesarean delivery are often delivered early by cesarean due to concern for uterine rupture. Although theoretically at increased risk for placenta accreta, this risk has not been well quantified. Our objective was to estimate and compare the risks of uterine rupture and placenta accreta in women with prior uterine surgery. Methods—Women with prior myomectomy or prior classical cesarean delivery were compared to women with a prior low transverse cesarean to estimate rates of both uterine rupture and placenta accreta. Results—One hundred seventy-six women with a prior myomectomy, 455 with a prior classical cesarean delivery, and 13,273 women with a prior low transverse cesarean were evaluated. Mean gestational age at delivery differed by group (p0.99) or in the prior classical cesarean delivery group (0.88%, p=0.13). Placenta accreta occurred in 0% (95% CI 0-1.98%) of prior myomectomy compared with 0.19% in the low transverse cesarean group (p>0.99) and 0.88% in the prior classical cesarean delivery group (p=0.01 relative to low transverse cesarean). The adjusted OR for the prior classical cesarean delivery group (relative to low transverse cesarean) was 3.23 (1.11-9.39) for uterine rupture and 2.09 (0.69-6.33) for accreta. The frequency of accreta for those with previa was 11.1% for the prior classical cesarean delivery and 13.6% for low transverse cesarean groups (p>0.99=1.0). Conclusion—A prior myomectomy is not associated with higher risks of either uterine rupture or placenta accreta. The absolute risks of uterine rupture and accreta after prior myomectomy are low

Consortium for the Study of Pregnancy Treatments (Co-OPT) : An international birth cohort to study the effects of antenatal corticosteroids

Acknowledgments We are grateful to the Co-OPT collaborators from Finland, Iceland, Israel, Nova Scotia, and Scotland, who have provided high-quality patient data, without which the Co-OPT ACS cohort would not have been possible. We acknowledge Public Health Scotland for providing us with a secure data analytical platform in which to undertake this research and are particularly grateful to Anna Schneider who has been the data controller for this project. Co-OPT collaborators: Karel Allegaert (Belgium), Jasper Been (Netherlands), David Burgner (Australia), Sohinee Bhattacharya (UK), Kate Duhig (UK), Kristjana Einarsdóttir (Iceland), John Fahey (Canada), Lani Florian (UK), Abigail Fraser (UK), Mika Gissler (Finland), Cynthia Gyamfi-Bannerman (USA), Bo Jacobsson (Sweden), Eyal Krispin (Israel), Stefan Kuhle (Canada), Marius Lahti-Pulkkinen (Finland), Jessica Miller (Australia), Ben Mol (Australia), Sarah Murray (UK), Jane Norman (UK), Lars Henning Pedersen (Denmark), Richard Riley (UK), Devender Roberts (UK), Ewoud Schuit (Netherlands), Aziz Sheikh (UK), Ting Shi (UK), Joshua Vogel (Australia), Rachael Wood (UK), John Wright (UK), Helga Zoega (Australia). Funding Information: The Co-OPT ACS study is funded through a Wellcome Trust Clinical Career Development Fellowship grant (Funding Reference number 209560/Z/17) awarded to Sarah J Stock. The funders had no role in study design, data collection, data analysis, decision to publish, or preparation of the manuscript. The Sponsor of the study is the University of Edinburgh (www.ed.ac. uk), Sponsor reference AC19119. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewedPublisher PD

Consortium for the Study of Pregnancy Treatments (Co-OPT): An international birth cohort to study the effects of antenatal corticosteroids

BACKGROUND: Antenatal corticosteroids (ACS) are widely prescribed to improve outcomes following preterm birth. Significant knowledge gaps surround their safety, long-term effects, optimal timing and dosage. Almost half of women given ACS give birth outside the "therapeutic window" and have not delivered over 7 days later. Overtreatment with ACS is a concern, as evidence accumulates of risks of unnecessary ACS exposure. METHODS: The Consortium for the Study of Pregnancy Treatments (Co-OPT) was established to address research questions surrounding safety of medications in pregnancy. We created an international birth cohort containing information on ACS exposure and pregnancy and neonatal outcomes by combining data from four national/provincial birth registers and one hospital database, and follow-up through linked population-level data from death registers and electronic health records. RESULTS AND DISCUSSION: The Co-OPT ACS cohort contains 2.28 million pregnancies and babies, born in Finland, Iceland, Israel, Canada and Scotland, between 1990 and 2019. Births from 22 to 45 weeks' gestation were included; 92.9% were at term (≥ 37 completed weeks). 3.6% of babies were exposed to ACS (67.0% and 77.9% of singleton and multiple births before 34 weeks, respectively). Rates of ACS exposure increased across the study period. Of all ACS-exposed babies, 26.8% were born at term. Longitudinal childhood data were available for 1.64 million live births. Follow-up includes diagnoses of a range of physical and mental disorders from the Finnish Hospital Register, diagnoses of mental, behavioural, and neurodevelopmental disorders from the Icelandic Patient Registers, and preschool reviews from the Scottish Child Health Surveillance Programme. The Co-OPT ACS cohort is the largest international birth cohort to date with data on ACS exposure and maternal, perinatal and childhood outcomes. Its large scale will enable assessment of important rare outcomes such as perinatal mortality, and comprehensive evaluation of the short- and long-term safety and efficacy of ACS

Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep

BackgroundAntenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure.ObjectiveThe purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep.Study designGroups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone-acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone-phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone-acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours.ResultsAll betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone-acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg.ConclusionA single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone-acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus