Risk of Adverse Obstetric and Neonatal Outcomes by Maternal Age: Quantifying Individual and Population Level Risk Using Routine UK Maternity Data.

OBJECTIVE: The objective of this study was to investigate whether moderately increased maternal age is associated with obstetric and neonatal outcome in a contemporary population, and to consider the possible role of co-morbidities in explaining any increased risk. STUDY DESIGN: Secondary analysis of routinely collected data from a large maternity unit in London, UK. Data were available on 51,225 singleton deliveries (≥22 weeks) occurring to women aged ≥20 between 2004 and 2012. Modified Poisson regression was used to estimate risk ratios for the association between maternal age and obstetric and neonatal outcome (delivery type, postpartum haemorrhage, stillbirth, low birthweight, preterm birth, small for gestational age, neonatal unit admission), using the reference group 20-24 years. Population attributable fractions were calculated to quantify the population impact. RESULTS: We found an association between increasing maternal age and major postpartum haemorrhage (≥1000ml blood loss) (RR 1.36 95% CI 1.18-1.57 for age 25-29 rising to 2.41 95% CI 2.02-2.88 for age ≥40). Similar trends were observed for caesarean delivery, most notably for elective caesareans (RR 1.64 95% CI 1.36-1.96 for age 25-29 rising to 4.94 95% CI 4.09-5.96 for age ≥40). There was evidence that parity modified this association, with a higher prevalence of elective caesarean delivery in older nulliparous women. Women aged ≥35 were at increased risk of low birthweight and preterm birth. We found no evidence that the risk of stillbirth, small for gestational age, or neonatal unit admission differed by maternal age. CONCLUSIONS: Our results suggest a gradual increase in the risk of caesarean delivery and postpartum haemorrhage from age 25, persisting after taking into account maternal BMI, hypertension and diabetes. The risk of low birthweight and preterm birth was elevated in women over 35. Further research is needed to understand the reasons behind the high prevalence of elective caesarean delivery in nulliparous older mothers

Inhibition of IL-34 Unveils Tissue-Selectivity and Is Sufficient to Reduce Microglial Proliferation in a Model of Chronic Neurodegeneration

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer´s disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cell types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF-1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signalling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in the the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophage populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34. Overall, our results highlight the challenges of targeting the CSF1R/IL34 axis in the systemic and central compartments, important for framing any therapeutic effort to tackle microglia/macrophage numbers during brain disease

CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer’s disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer’s disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer’s disease and other tau-mediated neurodegenerative diseases

Interaction between maternal age and parity.

<p>Interaction between maternal age and parity.</p

Obstetric and neonatal outcomes by maternal age category.

<p>Obstetric and neonatal outcomes by maternal age category.</p

Unadjusted and adjusted risk ratios for the association between maternal age and obstetric and neonatal outcome¹.

<p>Unadjusted and adjusted risk ratios for the association between maternal age and obstetric and neonatal outcome<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164462#t003fn001" target="_blank">¹</a>.</p

Risk of Adverse Obstetric and Neonatal Outcomes by Maternal Age: Quantifying Individual and Population Level Risk Using Routine UK Maternity Data

<div><p>Objective</p><p>The objective of this study was to investigate whether moderately increased maternal age is associated with obstetric and neonatal outcome in a contemporary population, and to consider the possible role of co-morbidities in explaining any increased risk.</p><p>Study Design</p><p>Secondary analysis of routinely collected data from a large maternity unit in London, UK. Data were available on 51,225 singleton deliveries (≥22 weeks) occurring to women aged ≥20 between 2004 and 2012. Modified Poisson regression was used to estimate risk ratios for the association between maternal age and obstetric and neonatal outcome (delivery type, postpartum haemorrhage, stillbirth, low birthweight, preterm birth, small for gestational age, neonatal unit admission), using the reference group 20–24 years. Population attributable fractions were calculated to quantify the population impact.</p><p>Results</p><p>We found an association between increasing maternal age and major postpartum haemorrhage (≥1000ml blood loss) (RR 1.36 95% CI 1.18–1.57 for age 25–29 rising to 2.41 95% CI 2.02–2.88 for age ≥40). Similar trends were observed for caesarean delivery, most notably for elective caesareans (RR 1.64 95% CI 1.36–1.96 for age 25–29 rising to 4.94 95% CI 4.09–5.96 for age ≥40). There was evidence that parity modified this association, with a higher prevalence of elective caesarean delivery in older nulliparous women. Women aged ≥35 were at increased risk of low birthweight and preterm birth. We found no evidence that the risk of stillbirth, small for gestational age, or neonatal unit admission differed by maternal age.</p><p>Conclusions</p><p>Our results suggest a gradual increase in the risk of caesarean delivery and postpartum haemorrhage from age 25, persisting after taking into account maternal BMI, hypertension and diabetes. The risk of low birthweight and preterm birth was elevated in women over 35. Further research is needed to understand the reasons behind the high prevalence of elective caesarean delivery in nulliparous older mothers.</p></div

Maternal characteristics by maternal age category.

<p>Maternal characteristics by maternal age category.</p

Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjögren's syndrome.

BACKGROUND The phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies. Primary Sjögren's syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration and B-cell hyperactivation which results in systemic manifestations, autoantibody production and loss of glandular function. Given the central role of B cells in pSS pathogenesis, we investigated PI3Kδ pathway activation in pSS and the functional consequences of blocking PI3Kδ in a murine model of focal sialoadenitis that mimics some features of pSS. METHODS AND RESULTS Target validation assays showed significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the phosphatidylinositol 3-kinase delta (PI3Kδ) pathway, within pSS salivary glands. pS6 distribution was found to co-localise with T/B cell markers within pSS aggregates and the CD138+ plasma cells infiltrating the glands. In vivo blockade of PI3Kδ activity with seletalisib, a PI3Kδ-selective inhibitor, in a murine model of focal sialoadenitis decreased accumulation of lymphocytes and plasma cells within the glands of treated mice in the prophylactic and therapeutic regimes. Additionally, production of lymphoid chemokines and cytokines associated with ectopic lymphoneogenesis and, remarkably, saliva flow and autoantibody production, were significantly affected by treatment with seletalisib. CONCLUSION These data demonstrate activation of PI3Kδ pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kδ pathway inhibition in this condition

Restoration of Cyclo-Gly-Pro-induced salivary hyposecretion and submandibular composition by naloxone in mice.

Cyclo-Gly-Pro (CGP) attenuates nociception, however its effects on salivary glands remain unclear. In this study, we investigated the acute effects of CGP on salivary flow and composition, and on the submandibular gland composition, compared with morphine. Besides, we characterized the effects of naloxone (a non-selective opioid receptor antagonist) on CGP- and morphine-induced salivary and glandular alterations in mice. After that, in silico analyses were performed to predict the interaction between CGP and opioid receptors. Morphine and CGP significantly reduced salivary flow and total protein concentration of saliva and naloxone restored them to the physiological levels. Morphine and CGP also reduced several infrared vibrational modes (Amide I, 1687-1594cm-1; Amide II, 1594-1494cm-1; CH2/CH3, 1488-1433cm-1; C = O, 1432-1365cm-1; PO2 asymmetric, 1290-1185cm-1; PO2 symmetric, 1135-999cm-1) and naloxone reverted these alterations. The in silico docking analysis demonstrated the interaction of polar contacts between the CGP and opioid receptor Cys219 residue. Altogether, we showed that salivary hypofunction and glandular changes elicited by CGP may occur through opioid receptor suggesting that the blockage of opioid receptors in superior cervical and submandibular ganglions may be a possible strategy to restore salivary secretion while maintaining antinociceptive action due its effects on the central nervous system