Spontaneous pregnancy loss mediated by abnormal maternal inflammation in rats is linked to deficient uteroplacental perfusion

Abnormal maternal inflammation during pregnancy is associated with spontaneous pregnancy loss and intrauterine fetal growth restriction. However, the mechanisms responsible for these pregnancy outcomes are not well understood. In this study, we used a rat model to demonstrate that pregnancy loss resulting from aberrant maternal inflammation is closely linked to deficient placental perfusion. Administration of LPS to pregnantWistar rats on gestational day 14.5, to induce maternal inflammation, caused fetal loss in a dose-dependent manner 3-4 h later, and surviving fetuses were significantly growth restricted. Pregnancy loss was associated with coagulopathy, structural abnormalities in the uteroplacental vasculature, decreased placental blood flow, and placental and fetal hypoxia within 3 h of LPS administration. This impairment in uteroplacental hemodynamics in LPS-treated rats was linked to increased uterine artery resistance and reduced spiral arteriole flow velocity. Pregnancy loss induced by LPS was prevented by maternal administration of the immunoregulatory cytokine IL-10 or by blocking TNF-α activity after treatment with etanercept (Enbrel). These results indicate that alterations in placental perfusion are responsible for fetal morbidities associated with aberrant maternal inflammation and support a rationale for investigating a potential use of immunomodulatory agents in the prevention of spontaneous pregnancy loss. Copyright © 2011 by The American Association of Immunologists, Inc

Tissue-Resident and Recruited Macrophages in Primary Tumor and Metastatic Microenvironments: Potential Targets in Cancer Therapy

Macrophages within solid tumors and metastatic sites are heterogenous populations with different developmental origins and substantially contribute to tumor progression. A number of tumor-promoting phenotypes associated with both tumor- and metastasis-associated macrophages are similar to innate programs of embryonic-derived tissue-resident macrophages. In contrast to recruited macrophages originating from marrow precursors, tissue-resident macrophages are seeded before birth and function to coordinate tissue remodeling and maintain tissue integrity and homeostasis. Both recruited and tissue-resident macrophage populations contribute to tumor growth and metastasis and are important mediators of resistance to chemotherapy, radiation therapy, and immune checkpoint blockade. Thus, targeting various macrophage populations and their tumor-promoting phenotypes holds therapeutic promise. Here, we discuss various macrophage populations as regulators of tumor progression, immunity, and immunotherapy. We provide an overview of macrophage targeting strategies, including therapeutics designed to induce macrophage depletion, impair recruitment, and induce repolarization. We also provide a perspective on the therapeutic potential for macrophage-specific acquisition of trained immunity as an anti-cancer agent and discuss the therapeutic potential of exploiting macrophages and their traits to reduce tumor burden

A dataset for the development and optimization of fall detection algorithms based on wearable sensors

This paper describes a dataset acquired on 8 subjects while simulating 13 types of falls and 5 types of Activities of Daily Living (ADL), each repeated 3 times. In details, data includes 4 simulated falls forward (falling on knees ending up lying, ending in lateral position, ending up lying, ending up lying with recovery), 4 backward (falling sitting ending up lying, ending in lateral position, ending up lying, ending up lying with recovery), 2 lateral right (ending up lying, ending up lying with recovery), 2 lateral left (ending up lying, ending up lying with recovery), and 1 syncope. Simulated ADL are: lying on a bed then standing; walking a few meters; sitting on a chair then standing; go up or down three steps; and standing after picking something. Data were acquired using a MARG sensor, a wearable multisensory device tied to the subject's waist, that recorded time-variations of the subject's acceleration and orientation (expressed through the yaw, pitch and roll angles). These data can be useful in the development and test of algorithms to automatically identify and classify fall events. Fall detection systems are particularly useful when a subject is alone and not able to stand up after a fall, since an automatic alarm can be sent remotely to receive proper help. Keywords: Human fall, Fall detection, MARG (Magnetic Angular Rate and Gravity) sensor, Wearable devic

Cross-Generational Impact of Innate Immune Memory Following Pregnancy Complications

Pregnancy complications can have long-term negative effects on the health of the affected mothers and their children. In this review, we highlight the underlying inflammatory etiologies of common pregnancy complications and discuss how aberrant inflammation may lead to the acquisition of innate immune memory. The latter can be described as a functional epigenetic reprogramming of innate immune cells following an initial exposure to an inflammatory stimulus, ultimately resulting in an altered response following re-exposure to a similar inflammatory stimulus. We propose that aberrant maternal inflammation associated with complications of pregnancy increases the cross-generational risk of developing noncommunicable diseases (i.e., pregnancy complications, cardiovascular disease, and metabolic disease) through a process mediated by innate immune memory. Elucidating a role for innate immune memory in the cross-generational health consequences of pregnancy complications may lead to the development of novel strategies aimed at reducing the long-term risk of disease

Inflammation-induced fetal growth restriction in rats is associated with increased placental HIF-1α accumulation

<div><p>Introduction</p><p>Hypoxia-inducible factor 1-alpha (HIF-1α) is the oxygen-sensitive subunit of the transcription factor HIF-1, and its expression is increased in placentas from pregnancies complicated by pre-eclampsia (PE). Fetal growth restriction (FGR) and PE often share a common pathophysiology; however, it is unknown whether increased placental HIF-1α occurs in FGR. We previously demonstrated that aberrant maternal inflammation in rats resulted in altered utero-placental perfusion and FGR, both of which were prevented by administration of the nitric oxide mimetic glyceryl trinitrate (GTN). Our aim here was to determine whether abnormal maternal inflammation causing FGR is linked to placental HIF-1α accumulation and whether GTN administration could prevent increases in placental HIF-1α.</p><p>Methods</p><p>Levels of inflammatory factors in maternal plasma were measured using a multiplex assay after an injection of low-dose lipopolysaccharide (LPS) to rats on gestational day (GD) 13.5. Following three additional daily LPS injections from GD14.5–16.5, GD17.5 placentas were harvested for HIF-1α immunolocalisation; serial sections were also stained for the hypoxia marker pimonidazole. A subset of rats received LPS injections along with GTN delivered continuously (25 μg/h via a transdermal patch) on GD12.5-GD17.5.</p><p>Results</p><p>Within two hours of LPS administration, levels of maternal pro-inflammatory cytokines were increased compared with saline-treated controls. GD17.5 placentas of growth-restricted fetuses exhibited increased HIF-1α accumulation; however, this did not correlate with pimonidazole staining for which no differences were observed between groups. Furthermore, the LPS-mediated increases in maternal inflammatory cytokine levels and placental HIF-1α accumulation did not occur in rats treated with GTN.</p><p>Discussion</p><p>Our results demonstrate that inflammation-induced FGR is associated with increased placental HIF-1α accumulation; however, expression of this transcription factor may not correlate with regions of hypoxia in late-gestation placentas. The GTN-mediated attenuation of placental HIF-1α accumulation in LPS-treated rats provides insight into the mechanism by which GTN improves inflammation-induced complications of pregnancy.</p></div

T-Wave Alternans in Partial Epileptic Patients

Epilepsy is a chronic neurological disorder, hallmark of which is unpredictable epileptic seizures (ES). The leading cause of death in people with uncontrolled ES is the sudden unexpected death in epilepsy (SUDEP), which is believed to share genes with sudden cardiac death (SCD). Being T-wave alternans (TWA) an ECG index of SCD, aim of this work was to evaluate TWA occurrence in proximity of ES. Electrocardiograms (ECG) from five partial epileptic patients constituting the “Post-Ictal Heart Rate Oscillations in Partial Epilepsy” Database by Physionet were analysed for automatic TWA identification by the heart-rate adaptive match filter (HRAMF). ES onsets and offsets were annotated. ECG segments starting 10min before ES and ending 10min after ES were extracted and further processed to characterize trends of median heart rate, median TWA (mTWA) and maximum TWA (MTWA) in ES proximity. Levels of mTWA were significantly higher than what previously observed in a female healthy population in all ES (46[25;59]µV), pre-ES (31[25;62]µV) and post-ES (30[26;63]µV) conditions. Both mTWA and MTWA tended to increase during ES. Thus, in proximity of ES, our epileptic patients are at increased risk of SCD, possibly associated with SUDEP. Other studies defining TWA role as a biomarker for SUDEP are needed