Placental Iron Content is Lower than Previously Estimated and is Associated with Maternal Iron Status in Women at Greater Risk for Gestational Iron Deficiency and Anemia

Background Based on limited data, it is estimated that the placenta retains 90 mg of iron (Fe). Little is known about determinants of placental Fe content. Animal data indicate that the placenta prioritizes Fe for its own needs, but this hypothesis has not been evaluated in humans. Objectives To characterize placental Fe content and placental Fe concentration (p[Fe]) in pregnant women at risk of Fe insufficiency and identify determinants of p[Fe]. Methods Placentae were collected from 132 neonates born to teens carrying singletons (≤18 y) and 101 neonates born to 48 women carrying multiples (20–46 y). Maternal and neonatal Fe status indicators (hemoglobin, SF, sTfR, serum Fe, TBI) and hormones (erythropoietin, hepcidin) were measured. P[Fe] was measured using ICP-MS. Correlation analyses and mixed-effects models were constructed to identify determinants of p[Fe]. Results Mean placental Fe content was 23 mg per placenta [95%CI 15–33] in the multiples and 40 mg [95%CI 31–51] in the teens (P = 0.03). Mean p[Fe] did not differ between the cohorts. P[Fe] was higher in anemic (175 [95%CI 120–254] μg/g) compared to non-anemic (46 [95%CI 26–82] μg/g) women carrying multiples (P = 0.009), but did not differ between anemic (62 [95%CI 40–102] μg/g) and non-anemic (73 [95%CI 56–97] μg/g) teens. In women carrying multiples, low maternal Fe status [lower SF (P = 0.002) and lower TBI (P = 0.01)] was associated with higher p[Fe], while in teens, improved Fe status [lower sTfR (P = 0.03) and higher TBI (P = 0.03)] was associated with higher p[Fe]. Conclusions Placental Fe content was ∼50% lower than previously estimated. P[Fe] is significantly associated with maternal Fe status. In women carrying multiples, poor maternal Fe status was associated with higher p[Fe], while in teens, improved Fe status was associated with higher p[Fe]. More data are needed to understand determinants of p[Fe] and the variable Fe partitioning in teens compared to mature women. Clinical Trial Registry: These clinical trials were registered at clinicaltrials.gov as NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902) and NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802).

Introduction to the Special LDLensRad Focus Issue

Recent epidemiological and experimental animal data, as well as reanalyses of data previously accumulated, indicate that the lens of the eye is more radiosensitive than was previously thought. This has resulted in a reduction of the occupational lens dose limit within the European Union countries, Japan and elsewhere. This Commentary introduces the work done by the LDLensRad Consortium contained within this Focus Issue, towards advancement of understanding of the mechanisms of low dose radiation cataract.

A model for learning based on the joint estimation of stochasticity and volatility

Previous research has stressed the importance of uncertainty for controlling the speed of learning, and how such control depends on the learner inferring the noise properties of the environment, especially volatility: the speed of change. However, learning rates are jointly determined by the comparison between volatility and a second factor, moment-to-moment stochasticity. Yet much previous research has focused on simplified cases corresponding to estimation of either factor alone. Here, we introduce a learning model, in which both factors are learned simultaneously from experience, and use the model to simulate human and animal data across many seemingly disparate neuroscientific and behavioral phenomena. By considering the full problem of joint estimation, we highlight a set of previously unappreciated issues, arising from the mutual interdependence of inference about volatility and stochasticity. This interdependence complicates and enriches the interpretation of previous results, such as pathological learning in individuals with anxiety and following amygdala damage.

Green Tea-Derived Theabrownin Induces Cellular Senescence and Apoptosis of Hepatocellular Carcinoma via P53 Signaling-Mediated Mechanism Bypassed by JNK Regulation

Background: Theabrownin (TB) is a bioactive component of tea and has been reported to exert effects against many human cancers, but its efficacy and mechanism on hepatocellular carcinoma (HCC) with different p53 genotypes remains unclarified. Methods: MTT assay, DAPI staining, flow cytometry and SA-β-gal staining were applied to evaluate the effects of TB on HCC cells. Quantitative real time PCR (qPCR) and Western blot (WB) were conducted to explore the molecular mechanism of TB. And xenograft model of zebrafish was established to evaluate the anti-tumor effect of TB.Results: MTT assays showed that TB significantly inhibited the proliferation of SK-Hep-1, HepG2, and Huh7 cells in a dose-dependent manner, of which SK-Hep-1 was the most sensitive one with the lowest IC50 values. The animal data showed that TB remarkably suppressed SK-Hep-1 tumor growth in xenograft model of zebrafish. The cellular data showed TB′s pro-apoptotic and pro-senescent effect on SK-Hep-1 cells. The molecular results revealed the mechanism of TB that p53 signaling pathway (p-ATM, p-ATR, γ-H2AX, p-Chk2, and p-p53) was activated with up-regulation of downstream senescent genes (P16, P21, IL-6 and IL-8) as well as apoptotic genes (Bim, Bax and PUMA) and proteins (Bax, c-Casp9 and c-PARP). The p53-mediated mechanism was verified by using p53-siRNA. Moreover, by using JNK-siRNA, we found JNK as a bypass regulator in TB′s mechanism. Conclusions: To sum up, TB exerted tumor-inhibitory, pro-senescent and pro-apoptotic effects on SK-Hep-1 cells through ATM-Chk2-p53 signaling axis in accompany with JNK bypass regulation. This is the first report on the pro-senescent effect and multi-target (p53 and JNK) mechanism of TB on HCC cells, providing new insights into the underlying mechanisms of TB′s anti-HCC efficacy.

150. Updated Clinical Guidelines for Treatment and Prophylaxis of Plague

Background Plague still occurs naturally in the western United States, Latin America, Asia, and Africa. Yersinia pestis, the causative agent of plague, is a Tier 1 bioterrorism agent due to its potential for aerosol release and high fatality rates. Recommendations for treatment and post-exposure prophylaxis (PEP) of plague were published in 2000 and included limited first-line options for treating plague, namely streptomycin or gentamicin. Doxycycline or ciprofloxacin were recommended for PEP. However, since 2000 new human clinical data and animal data have become available, and the FDA has approved additional antimicrobials for plague. Methods CDC developed updated, evidence-based guidelines for treatment and prophylaxis of plague using a comprehensive process. To collect evidence on relative efficacy of various antimicrobials for treatment of plague, the guidelines team conducted systematic literature reviews and analyzed U.S. surveillance data. Results of these investigations were published in Clinical Infectious Diseases in 2020. We also hosted several meetings with subject matter experts and clinical organizations (IDSA, AAP, etc.), federal agencies, and others to review relevant data and gather individual input on treatment and prophylaxis of plague. Results The forthcoming plague guidelines will include several important updates. First-line treatment options have been expanded to include ciprofloxacin, levofloxacin, and moxifloxacin in addition to streptomycin and gentamicin. For PEP, levofloxacin and moxifloxacin are now first-line options in addition to doxycycline and ciprofloxacin. Trimethoprim-sulfamethoxazole is now one of several new alternative options for PEP. The updated guidelines also include recommendations for treatment of clinical forms of plague other than pneumonic. Additional special populations such as immunocompromised persons and neonates are also covered. Conclusion Plague remains a threat, both as a naturally occurring disease and as a potential bioterrorism weapon, and preparedness and early recognition are key to effective response. The updated clinical guidelines will be a useful tool for clinicians to manage antimicrobial treatment and PEP for plague. Disclosures All Authors: No reported disclosures

Neuroprotective Agents for Neonates with Hypoxic-Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy (HIE) remains a significant source of long-term neurodevelopmental impairment despite overall improvements in survival without disability in neonates who undergo therapeutic hypothermia. Each phase in the evolution of hypoxic-ischemic injury presents potential pharmacologic targets for neuroprotective agents. Melatonin is a promising emerging therapy for early phases of ischemic injury, but utility is currently limited by the lack of pharmaceutical-grade products. Magnesium has been extensively studied for its neuroprotective effects in the preterm population. Studies in neonates with HIE have produced mixed outcomes. Erythropoietin use in HIE with or without therapeutic hypothermia appears to be safe and may provide additional benefit. Dexmedetomidine, N-acetylcysteine, xenon, and topiramate all have promising animal data, but need additional human trials to elucidate what role they may play in HIE. Frequent review of existing literature is required to ensure provision of evidence-based pharmacologic agents for neuroprotection following HIE.

Novel Insights into Pyrrolizidine Alkaloid Toxicity and Implications for Risk Assessment: Occurrence, Genotoxicity, Toxicokinetics, Risk Assessment–A Workshop Report

This paper reports on the major contributions and results of the 2nd International Workshop of Pyrrolizidine Alkaloids held in September 2020 in Kaiserslautern, Germany. Pyrrolizidine alkaloids are among the most relevant plant toxins contaminating food, feed, and medicinal products of plant origin. Hundreds of PA congeners with widespread occurrence are known, and thousands of plants are assumed to contain PAs. Due to certain PAsʼ pronounced liver toxicity and carcinogenicity, their occurrence in food, feed, and phytomedicines has raised serious human health concerns. This is particularly true for herbal teas, certain food supplements, honey, and certain phytomedicinal drugs. Due to the limited availability of animal data, broader use of in vitro data appears warranted to improve the risk assessment of a large number of relevant, 1,2-unsaturated PAs. This is true, for example, for the derivation of both toxicokinetic and toxicodynamic data. These efforts aim to understand better the modes of action, uptake, metabolism, elimination, toxicity, and genotoxicity of PAs to enable a detailed dose-response analysis and ultimately quantify differing toxic potencies between relevant PAs. Accordingly, risk-limiting measures comprising production, marketing, and regulation of food, feed, and medicinal products are discussed.

Transfer Function for Relative Blast Overpressure Through Porcine and Human Skulls In Situ

ABSTRACT Introduction The overarching objective of the Office of Naval Research sponsored Blast Load Assessment Sense and Test (BLAST) program was to quantify neurofunctional risk from repeated blast exposure. However, human studies have limitations in data collection that can only be addressed by animal models. To utilize a large animal model in this work, researchers developed an approach for scaling blast exposure data from animal to human-equivalent loading. For this study, energy interacting with the brain tissue was selected as a translation metric because of the hypothesized association between observed neurological changes and energy transmitted through the skull. This article describes the methodology used to derive an energy-based transfer function capable of serving as a global correspondence rule for primary blast injury exposure, allowing researchers to derive human-appropriate thresholds from animal data. Methods and Materials To generate data for the development of the transfer functions, three disarticulated cadaveric Yucatan minipigs and three postmortem human surrogate heads were exposed to blast overpressure using a large bore, compressed-gas shock tube. Pressure gauges in the free field, on the skull surface, and pressure probes within the brain cavity filled with Sylgard silicone gel recorded the pressure propagation through the skull of each specimen. The frequency components of the freefield and brain cavity measurements from the pig and human surrogates were interrogated in the frequency domain. Doing so quantifies the differences in the amount of energy, in each frequency band, transmitted through both the porcine and the human skull, and the transfer function was calculated to quantify those differences. Results Nonlinear energy transmission was observed for both the porcine and human skulls, indicating that linear scaling would not be appropriate for developing porcine to human transfer functions. This study demonstrated similar responses between species with little to no attenuation at frequencies below 30 Hz. The phase of the pressure transmission to the brain is also similar for both species up to approximately 10 kHz. There were two notable differences between the porcine and human surrogates. First, in the 40-100 Hz range, human subjects have approximately 8 dB more pressure transmitted through the skull relative to porcine subjects. Second, in the 1-10 kHz range, human subjects have up to 10 dB more pressure transmitted into the brain (10 dB more attenuation) relative to the porcine subjects. Conclusions The fundamental goal of this study was to develop pig-to-human transfer functions to allow researchers to interpret data collected from large animal studies and aid in deriving risk functions for repeated blast exposures. Similarities in porcine and human brain physiology make the minipig experimental model an excellent candidate for blast research. However, differences in the skull geometry have historically made the interpretation of animal data difficult for the purposes of characterizing potential neurological risk in humans. Human equivalent loading conditions are critical so that the thresholds are not over- or underpredicted due to differences in porcine skull geometry. This research provides a solution to this challenge, providing a robust methodology for interpreting animal data for blast research.